- DNA-Encoded Libraries: Hydrazide as a Pluripotent Precursor for On-DNA Synthesis of Various Azole Derivatives
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DNA-encoded combinatorial chemical library (DEL) technology, an approach that combines the power of genetics and chemistry, has emerged as an invaluable tool in drug discovery. Skeletal diversity plays a fundamental importance in DEL applications, and relies heavily on novel DNA-compatible chemical reactions. We report herein a phylogenic chemical transformation strategy using DNA-conjugated benzoyl hydrazine as a common versatile precursor in azole chemical expansion of DELs. DNA-compatible reactions deriving from the common benzoyl hydrazine precursor showed excellent functional group tolerance with exceptional efficiency in the synthesis of various azoles, including oxadiazoles, thiadiazoles, and triazoles, under mild reaction conditions. The phylogenic chemical transformation strategy provides DELs a facile way to expand into various unique chemical spaces with privileged scaffolds and pharmacophores.
- Ma, Fei,Li, Jie,Zhang, Shuning,Gu, Yuang,Tan, Tingting,Chen, Wanting,Wang, Shuyue,Ma, Peixiang,Xu, Hongtao,Yang, Guang,Lerner, Richard A.
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supporting information
p. 8214 - 8220
(2021/05/03)
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- Synthesis and antischistosomal activity of linker- and thiophene-modified biaryl alkyl carboxylic acid derivatives
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Schistosomiasis is a neglected tropical disease caused by blood flukes of the genus Schistosoma and causes severe morbidity in infected patients. In 2018, 290.8 million people required treatment, and 200,000 deaths are reported per year. Treatment of this disease depends on a single drug, praziquantel (PZQ). However, in the past few years, reduced sensitivity of the parasites toward PZQ has been reported. Therefore, there is an urgent need for new drugs against this disease. In the past few years, we have focused on a new substance class called biaryl alkyl carboxylic acid derivatives, which showed promising antischistosomal activity in vitro. Structure–activity relationship (SAR) studies of the carboxylic acid moiety led to three promising carboxylic amides (morpholine, thiomorpholine, and methyl sulfonyl piperazine) with an antischistosomal activity down to 10 μM (morpholine derivative) and no cytotoxicity up to 100 μM. Here, we show our continued work on this substance class. We investigated, in extended SAR studies, whether modification of the linker and the thiophene ring could improve the antischistosomal activity. We found that the exchange of the alkyl linker by a pentadienyl or benzyl linker was tolerated and led to similar antischistosomal effects, whereas the exchange of the thiophene ring was not tolerated. Our data suggest that the thiophene ring is important for the antischistosomal activity of this compound class.
- Peter Ventura, Alejandra M.,Haeberlein, Simone,Konopka, Leonie,Obermann, Wiebke,Grünweller, Arnold,Grevelding, Christoph G.,Schlitzer, Martin
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- Substitution Effect on 2-(Oxazolinyl)-phenols and 1,2,5-Chalcogenadiazole -Annulated Derivatives: Emission-Color-Tunable, Minimalistic Excited-State Intramolecular Proton Transfer (ESIPT)-Based Luminophores
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Minimalistic 2-(oxazolinyl)-phenols substituted with different electron-donating and -withdrawing groups as well as 1,2,5-chalcogenadiazole-annulated derivatives thereof were synthesized and investigated in regard to their emission behavior in solution as well as in the solid state. Depending on the nature of the incorporated substituent and its position, emission efficiencies were increased or diminished, resulting in AIE or ACQ characteristics. Single-crystal analysis revealed J- and H-type packing motifs and a so-far undescribed isolation of ESIPT-based fluorophores in the keto form.
- G?bel, Dominik,Rusch, Pascal,Duvinage, Daniel,Stauch, Tim,Bigall, Nadja-C.,Nachtsheim, Boris J.
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supporting information
p. 14333 - 14355
(2021/10/20)
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- Aziridine-2-carboxylic acid derivatives and its open-ring isomers as a novel PDIA1 inhibitors
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[Figure not available: see fulltext.] Acyl derivatives of aziridine-2-carboxylic acid have been synthesized and tested as PDIA1 inhibitors. Calculations of charge value and distribution in aziridine ring system and some alkylating agents were performed. For the first time was found that acyl derivatives of aziridine-2-carboxylic acid are weak to moderately active PDIA1 inhibitors.
- Leite, Irena,Andrianov, Victor,Zelencova-Gopejenko, Diana,Loza, Einars,Kazhoka-Lapsa, Iveta,Domracheva, Ilona,Stoyak, Marta,Chlopicki, Stefan,Kalvins, Ivars
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p. 1086 - 1106
(2022/01/12)
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- Bisubstrate inhibitors of nicotinamide N-methyltransferase (NNMT) with enhanced activity
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Nicotinamide N-methyltransferase (NNMT) catalyzes the methylation of nicotinamide to form N-methylnicotinamide. Overexpression of NNMT is associated with a variety of diseases, including a number of cancers and metabolic disorders, suggesting a role for NNMT as a potential therapeutic target. By structural modification of a lead NNMT inhibitor previously developed in our group, we prepared a diverse library of inhibitors to probe the different regions of the enzyme's active site. This investigation revealed that incorporation of a naphthalene moiety, intended to bind the hydrophobic nicotinamide binding pocket via π-πstacking interactions, significantly increases the activity of bisubstrate-like NNMT inhibitors (half-maximal inhibitory concentration 1.41 μM). These findings are further supported by isothermal titration calorimetry binding assays as well as modeling studies. The most active NNMT inhibitor identified in the present study demonstrated a dose-dependent inhibitory effect on the cell proliferation of the HSC-2 human oral cancer cell line.
- Gao, Yongzhi,Van Haren, Matthijs J.,Moret, Ed E.,Rood, Johannes J. M.,Sartini, Davide,Salvucci, Alessia,Emanuelli, Monica,Craveur, Pierrick,Babault, Nicolas,Jin, Jian,Martin, Nathaniel I.
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p. 6597 - 6614
(2019/08/20)
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- Functional Group Transposition: A Palladium-Catalyzed Metathesis of Ar-X σ-Bonds and Acid Chloride Synthesis
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We describe the development of a new method to use palladium catalysis to form functionalized aromatics: via the metathesis of covalent σ-bonds between Ar-X fragments. This transformation demonstrates the dynamic nature of palladium-based oxidative addition/reductive elimination and offers a straightforward approach to incorporate reactive functional groups into aryl halides through exchange reactions. The reaction has been exploited to assemble acid chlorides without the use of high energy halogenating or toxic reagents and, instead, via the metathesis of aryl iodides with other acid chlorides.
- De La Higuera Macias, Maximiliano,Arndtsen, Bruce A.
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supporting information
p. 10140 - 10144
(2018/08/23)
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- Copper-Catalyzed Enantioselective Alkylation of Enolizable Ketimines with Organomagnesium Reagents
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Inexpensive and readily available organomagnesium reagents were used for the catalytic enantioselective alkylation of enolizable N-sulfonyl ketimines. The low reactivity and competing enolization of the ketimines was overcome by the use of a copper–phosphine chiral catalyst, which also rendered the transformation highly chemoselective and enantioselective for a broad range of ketimine substrates.
- Ortiz, Pablo,Collados, Juan F.,Jumde, Ravindra P.,Otten, Edwin,Harutyunyan, Syuzanna R.
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supporting information
p. 3041 - 3044
(2017/03/14)
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- Cp?CoIII-Catalyzed syn-Selective C-H Hydroarylation of Alkynes Using Benzamides: An Approach Toward Highly Conjugated Organic Frameworks
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Hydroarylation of internal alkynes by cost-effective CoIII-catalysis, directed by N-tert-butyl amides, is achieved to avail mono- or dihydroarylated amide products selectively in an atom and step economic way. Several important functional groups were tolerated under the reaction conditions, and syn-hydroarylation products were exclusively isolated. Notably, a 4-fold C-H hydroarylation provided a highly conjugated organic framework in one step. Kinetic study with extensive deuterium labeling experiments were performed to support the proposed mechanism.
- Bera, Sourav Sekhar,Debbarma, Suvankar,Ghosh, Avick Kumar,Chand, Santanu,Maji, Modhu Sudan
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p. 420 - 430
(2017/04/26)
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- Heteroannulation enabled by a bimetallic Rh(III)/Ag(i) relay catalysis: Application in the total synthesis of aristolactam BII
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A redox-neutral bimetallic Rh(iii)/Ag(i) relay catalysis allowed the efficient construction of 3-alkylidene isoindolinones and 3-alkylidene isobenzofuranones. The Rh(iii) catalyst was responsible for the C-H monofluoroalkenylation reaction, whereas the Ag(i) salt was an activator for the follow-up cyclization. The methodology developed was applied as a key step in the rapid total synthesis of the natural product aristolactam BII.
- Ji, Wei-Wei,Lin,Li, Qingjiang,Wang, Honggen
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supporting information
p. 5665 - 5668
(2017/07/07)
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- Structure-activity relationship study of β-oxidation resistant indole-based 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) receptor antagonists
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5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is formed from 5S-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) by the 5-lipoxygenase (5-LO) pathway under conditions associated with oxidative stress. 5-Oxo-ETE is an important pro-inflammatory mediator, which stimulates the migration of eosinophils via a selective G-protein coupled receptor, known as the OXE receptor (OXE-R). Previously, we designed and synthesized structural mimics of 5-oxo-ETE such as 1 using an indole scaffold. In the present work, we added various substituents at C-3 of this moiety to block potential β-oxidation of the 5-oxo-valerate side chain, and investigated the structure-activity relationships of the resulting novel β-oxidation-resistant antagonists. Cyclopropyl and cyclobutyl substituents were well tolerated in this position, but were less potent as the highly active 3S-methyl compound. It seems likely that 3-alkyl substituents can affect the conformation of the 5-oxovalerate side chain containing the critical keto and carboxyl groups, thereby affecting interaction with the OXE-receptor.
- Ye, Qiuji,Chourey, Shishir,Wang, Rui,Chintam, Nagendra Reddy,Gravel, Sylvie,Powell, William S.,Rokach, Joshua
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supporting information
p. 4770 - 4776
(2017/09/27)
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- Compounds and methods for inhibiting phosphate transport
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Compounds having activity as phosphate transport inhibitors, more specifically, inhibitors of intestinal apical membrane Na/phosphate co-transport, are disclosed. The compounds have the following structure (I): including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein X, Y, A, R1 and R2 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Page/Page column 233; 234
(2016/05/02)
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- Design and synthesis of dihydroisoquinolones for fragment-based drug discovery (FBDD)
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This study describes general synthesis aspects of fragments for FBDD, as illustrated by the dihydroisoquinolones 1-3. Previous Rh(iii) methodology is extended to incorporate amines, heteroatoms (N and S), and substituents (halogen, ester) as potential binding groups and/or synthetic growth points for fragment-to-lead elaboration.
- Palmer, Nick,Peakman, Torren M.,Norton, David,Rees, David C.
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p. 1599 - 1610
(2016/02/10)
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- Induced europium CPL for the selective signalling of phosphorylated amino-acids and: O -phosphorylated hexapeptides
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Two bright, europium(iii) complexes based on an achiral heptadentate triazacyclononane ligand bearing two strongly absorbing chromophores have been evaluated for the selective emission and CPL signalling of various chiral O-phosphono-anions. Binding of O-
- Neil, Emily R.,Fox, Mark A.,Pal, Robert,Parker, David
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supporting information
p. 8355 - 8366
(2016/06/01)
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- One-pot synthetic method for m-acetylbenzoic acid
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The invention relates to a synthetic method, in particular to a one-pot synthetic method for m-acetylbenzoic acid. According to the one-pot synthetic method for the m-acetylbenzoic acid, there is no need to purify an intermediate product. The reaction equation of the m-acetylbenzoic acid is shown in the description, wherein R refers to methyl or ethyl, and R1 refers to methyl or ethyl or n-propyl. Compared with synthetic methods in the prior art, the synthetic method has the advantages that raw materials are low in price and easy to get, reaction conditions are mild, the obtained intermediate product can be directly used for a reaction in a next step without being separated and purified, and therefore process cost is greatly lowered.
- -
-
Paragraph 0031; 0032
(2016/10/10)
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- Ligand-promoted ortho-C-H amination with Pd catalysts
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2,4,6-Trimethoxypyridine is identified as an efficient ligand for promoting a Pd-catalyzed ortho-C-H amination of both benzamides and triflyl-protected benzylamines. This finding provides guidance for the development of ligands that can improve or enable PdII-catalyzed Csp2-H activation reactions directed by weakly coordinating functional groups.
- Zhu, Dajian,Yang, Guoqiang,He, Jian,Chu, Ling,Chen, Gang,Gong, Wei,Chen, Ke,Eastgate, Martin D.,Yu, Jin-Quan
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supporting information
p. 2497 - 2500
(2015/02/19)
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- Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors
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A new class of colchicine derivatives were designed and synthesized as tubulin-HDAC dual inhibitors. Biological evaluations of these hybrids included the inhibitory activity of HDAC, tubulin polymerization analysis, in vitro cell cycle analysis in HCT-116 cells and cytotoxicity against different cancer cell lines. Hybrid 6d behaved as potent HDAC-tubulin dual inhibitor and showed comparable cytotoxicity with colchicine. Compound 11a exhibited powerful tubulin inhibitory activity, moderate anti-HDAC activity and the most potent cytotoxicity (IC50 Combining double low line 2-105 nM).
- Zhang, Xuan,Kong, Yannan,Zhang, Jie,Su, Mingbo,Zhou, Yubo,Zang, Yi,Li, Jia,Chen, Yi,Fang, Yanfen,Zhang, Xiongwen,Lu, Wei
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p. 127 - 135
(2015/04/14)
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- NOVEL HETEROCYCLIC COMPOUNDS
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The present invention relates to novel GPR 40 agonists of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of the
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Page/Page column 38; 39
(2015/07/15)
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- A Mild and Regioselective Route to Functionalized Quinazolines
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A Rh-catalyzed ortho-amidation cyclocondensation sequence gave a range of 4-aminoquinazolines in high yield. The method features a remarkably mild C(sp2)-H activation step and can be exploited to rapidly access compounds with established biological activity.
- Maiden, Tracy M. M.,Swanson, Stephen,Procopiou, Panayiotis A.,Harrity, Joseph P. A.
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supporting information
p. 14342 - 14346
(2015/10/05)
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- Mild rhodium(III)-catalyzed C-H allylation with 4-vinyl-1,3-dioxolan-2-ones: Direct and stereoselective synthesis of (E)-allylic alcohols
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A rhodium(III)-catalyzed C-H direct allylation reaction with 4-vinyl-1,3-dioxolan-2-ones has been developed. The reaction provides a facile and stereoselective access to substituted-(E)-allylic alcohols under mild and redox-neutral reaction conditions. Olefinic C-H activation is applicable, giving multifunctionalized skipped dienes in good yields. Minimal double-bond migration was observed.
- Zhang, Shang-Shi,Wu, Jia-Qiang,Lao, Ye-Xing,Liu, Xu-Ge,Liu, Yao,Lv, Wen-Xin,Tan, Dong-Hang,Zeng, Yao-Fu,Wang, Honggen
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supporting information
p. 6412 - 6415
(2015/01/09)
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- Nitrate anion templated assembly of a [2]rotaxane for selective nitrate recognition in aqueous solvent mixtures
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The first nitrate anion templated assembly of an interlocked molecular architecture is demonstrated through the preparation of a [2]rotaxane. Removal of the discrete nitrate anion template from the [2]rotaxane reveals an interlocked host system capable of
- Langton, Matthew J.,Duckworth, Lucy C.,Beer, Paul D.
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supporting information
p. 8608 - 8610
(2013/09/23)
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- A palladium-catalyzed carbonylation approach to acid chloride synthesis
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We describe a new approach to acid chloride synthesis via the palladium-catalyzed carbonylation of aryl iodides. The combination of sterically encumbered phosphines (PtBu3) and CO coordination has been found to facilitate the rapid carbonylation of aryl iodides into acid chlorides via reductive elimination from (tBu3P)(CO) Pd(COAr)Cl. The formation of acid chlorides can also be exploited to perform traditional aminocarbonylation reactions under exceptionally mild conditions (ambient temperature and pressure), and with a range of weakly nucleophilic substrates.
- Quesnel, Jeffrey S.,Arndtsen, Bruce A.
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supporting information
p. 16841 - 16844
(2013/12/04)
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- COMPOUNDS AND METHODS FOR INHIBITING PHOSPHATE TRANSPORT
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Compounds having activity as phosphate transport inhibitors, more specifically, inhibitors of intestinal apical membrane Na/phosphate co-transport, are disclosed. The compounds have the following structure (I): including stereoisomers, pharmaceutically ac
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Page/Page column 71
(2012/02/01)
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- COMPOUNDS AND METHODS FOR INHIBITING PHOSPHATE TRANSPORT
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Compounds having activity as phosphate transport inhibitors, more specifically, inhibitors of intestinal apical membrane Na/phosphate co-transport, are disclosed. The compounds have the following structure (I): including stereoisomers, pharmaceutically ac
- -
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Page/Page column 45
(2012/02/01)
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- COMPOUNDS AND METHODS FOR INHIBITING PHOSPHATE TRANSPORT
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Compounds having activity as phosphate transport inhibitors, more specifically, inhibitors of intestinal apical membrane Na/phosphate co-transport, are disclosed. The compounds have the following structure (I): including stereoisomers, pharmaceutically ac
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Page/Page column 52
(2012/02/01)
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- NOVEL COMPOUNDS
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Disclosed are retinoid-related orphan receptor gamma (RORγ) modulators and their use in the treatment of diseases mediated by RORγ.
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Page/Page column 64
(2012/03/26)
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- NITROGEN RING CONTAINING COMPOUNDS FOR TREATMENT OF INFLAMMATORY DISORDERS
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The invention provides compounds, pharmaceutical compositions and methods of treatment of inflammatory disorders including a compound of Formula I, or its pharmaceutically acceptable salt, ester, pharmaceutically acceptable derivative or prodrug wherein R
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Page/Page column 194
(2012/10/18)
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- PIPERIDINE AMIDES AS MODULATORS OF THE GHRELIN RECEPTOR
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Compounds of formula (I) or pharmaceutically acceptable salts thereof, are useful for the treatment of diabetes and obesity.
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Page/Page column 43-44
(2011/10/13)
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- An efficient synthesis of futalosine
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Futalosine is a naturally occurring nucleoside comprised of an inosine core with a 3-carboxyphenyl methylene ketone functionality replacing the C-5′ hydroxyl. Recent studies have shown that it is a key intermediate in an alternative biosynthetic pathway that generates menaquinone in a variety of bacterial species. Here we report the first synthesis of futalosine in seven steps from inosine in an overall 17% yield. This work will enable further studies on menaquinone biosynthesis in pathogenic bacteria.
- Li, Xu,Tanner, Martin E.
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supporting information; experimental part
p. 6463 - 6465
(2010/12/25)
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- Design and synthesis of 2-arylbenzimidazoles and evaluation of their inhibitory effect against Chlamydia pneumoniae
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Chlamydia pneumoniae is an intracellular bacterium that responds poorly to antibiotic treatment. Insufficient antibiotic usage leads to chronic infection, which is linked to disease processes of asthma, atherosclerosis, and Alzheimer's disease. The Chlamydia research lacks genetic tools exploited by other antimicrobial research, and thus other approaches to drug discovery must be applied. A set of 2-arylbenzimidazoles was designed based on our earlier findings, and 33 derivatives were synthesized. Derivatives were assayed against C. pneumoniae strain CWL-029 in an acute infection model using TR-FIA method at a concentration of 10 μM, and the effects of the derivatives on the host cell viability were evaluated at the same concentration. Fourteen compounds showed at least 80% inhibition, with only minor changes in host cell viability. Nine most potential compounds were evaluated using immunofluorescence microscopy on two different strains of C. pneumoniae CWL-029 and CV-6. The N-[3-(1H-benzimidazol-2-yl)phenyl]-3-methylbenzamide (42) had minimal inhibitory concentration (MIC) of 10 μM against CWL-029 and 6.3 μM against the clinical strain CV-6. This study shows the high antichlamydial potential of 2-arylbenzimidazoles, which also seem to have good characteristics for lead compounds.
- Keurulainen, Leena,Salin, Olli,Siiskonen, Antti,Kern, Jan Marco,Alvesalo, Joni,Kiuru, Paula,Maass, Matthias,Yli-Kauhaluoma, Jari,Vuorela, Pia
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supporting information; experimental part
p. 7664 - 7674
(2011/03/17)
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- THIAZOLE AND OXAZOLE KINASE INHIBITORS
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The present invention provides thiazole and oxazole compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.
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Page/Page column 197
(2009/07/17)
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- FARNESOID X RECEPTOR AGONISTS
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The present invention relates to famesoid X receptors (FXR, NR1H4) FXR is a member of the nuclear receptor class of ligand-activate transcription factors More particularly, the present invention relates to compounds useful as agonists for FXR, pharmaceutical formulations comprising such compounds, and therapeutic use of the same Novel isoxazole compounds are disclosed as part of pharmaceutical compositions for the treatment of a condition mediated by decreased FXR activity, such as obesity, diabetes, cholestatic liver disease, liver fibrosis, and metabolic syndrome
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Page/Page column 112
(2009/03/07)
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- Toward optimization of the second aryl substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies
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Transthyretin (TTR) amyloidogenesis inhibitors are typically composed of two aromatic rings and a linker. We have previously established optimal structures for one aromatic ring and the linker. Herein, we employ a suboptimal linker and an optimal aryl-X substructure to rank order the desirability of aryl-Z substructures-using a library of 56 N-(3,5-dibromo-4-hydroxyphenyl) benzamides. Coconsideration of amyloid inhibition potency and ex vivo plasma TTR binding selectivity data reveal that 2,6, 2,5, 2, 3,4,5, and 3,5 substituted aryls bearing small substituents generate the most potent and selective inhibitors, in descending order. These benzamides generally lack undesirable thyroid hormone receptor binding and COX-1 inhibition activity. Three high-resolution TTR ? inhibitor crystal structures (1.31-1.35 ?) provide insight into why these inhibitors are potent and selective, enabling future structure-based design of TTR kinetic stabilizers.
- Johnson, Steven M.,Connelly, Stephen,Wilson, Ian A.,Kelly, Jeffery W.
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supporting information; experimental part
p. 1115 - 1125
(2009/12/24)
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- Modeling, synthesis and biological evaluation of potential Retinoid X Receptor (RXR) selective agonists: Novel analogues of 4-[1-(3,5,5,8,8- pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene)
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This report describes the synthesis of analogues of 4-[1-(3,5,5,8,8- pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), commonly known as bexarotene, and their analysis in acting as retinoid X receptor (RXR)-specific agonists. Compound 1 has FDA approval to treat cutaneous T-cell lymphoma (CTCL); however, its use can cause side effects such as hypothyroidism and increased triglyceride concentrations, presumably by disruption of RXR heterodimerization with other nuclear receptors. The novel analogues in the present study have been evaluated forRXR activation in an RXR mammalian-2-hybrid assay as well as an RXRE-mediated transcriptional assay and for their ability to induce apoptosis as well as for their mutagenicity and cytotoxicity. Analysis of 11 novel compounds revealed the discovery of three analogues that best induce RXR-mediated transcriptional activity, stimulate apoptosis, have comparable Ki and EC50 values to 1, and are selective RXR agonists. Our experimental approach suggests that rational drug design can develop new rexinoids with improved biological properties. 2009 American Chemical Society.
- Wagner, Carl E.,Jurutka, Peter W.,Marshall, Pamela A.,Groy, Thomas L.,Van Der Vaart, Arjan,Ziller, Joseph W.,Furmick, Julie K.,Graeber, Mark E.,Matro, Erik,Miguel, Belinda V.,Tran, Ivy T.,Kwon, Jungeun,Tedeschi, Jamie N.,Moosavi, Shahram,Danishyar, Amina,Philp, Joshua S.,Khamees, Reina O.,Jackson, Jevon N.,Grupe, Darci K.,Badshah, Syed L.,Hart, Justin W.
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experimental part
p. 5950 - 5966
(2010/02/28)
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- Discovery and optimization of imidazo[1,2-a]pyridine inhibitors of insulin-like growth factor-1 receptor (IGF-1R)
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The optimization of imidazo[1,2-a]pyridine inhibitors as potent and selective inhibitors of IGF-1R is presented. Further optimization of oral exposure in mice is also discussed. Detailed selectivity, in vitro activity, and in vivo PK profiles of an optimi
- Emmitte, Kyle A.,Wilson, Brian J.,Baum, Erich W.,Emerson, Holly K.,Kuntz, Kevin W.,Nailor, Kristen E.,Salovich, James M.,Smith, Stephon C.,Cheung, Mui,Gerding, Roseanne M.,Stevens, Kirk L.,Uehling, David E.,Mook Jr., Robert A.,Moorthy, Ganesh S.,Dickerson, Scott H.,Hassell, Anne M.,Anthony Leesnitzer,Shewchuk, Lisa M.,Groy, Arthur,Rowand, Jason L.,Anderson, Kelly,Atkins, Charity L.,Yang, Jingsong,Sabbatini, Peter,Kumar, Rakesh
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scheme or table
p. 1004 - 1008
(2009/10/15)
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- Aroylguanidine-based factor Xa inhibitors: The discovery of BMS-344577
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We report the design and synthesis of a novel class of N,N′-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure-activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC50 = 4 nM, EC2×PT = 7 μM). However, the potent CYP3A4 inhibition activity (IC50 = 0.3 μM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC50 = 9 nM, EC2×PT = 2.5 μM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models.
- Shi, Yan,Li, Chi,O'Connor, Stephen P.,Zhang, Jing,Shi, Mengxiao,Bisaha, Sharon N.,Wang, Ying,Sitkoff, Doree,Pudzianowski, Andrew T.,Huang, Christine,Klei, Herbert E.,Kish, Kevin,Yanchunas Jr., Joseph,Liu, Eddie C.-K.,Hartl, Karen S.,Seiler, Steve M.,Steinbacher, Thomas E.,Schumacher, William A.,Atwal, Karnail S.,Stein, Philip D.
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scheme or table
p. 6882 - 6889
(2010/07/03)
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- Synthesis and antiplatelet activity of ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3) derivatives
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Previously, ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3) was identified by us as the first non-peptide protease-activated receptor 4 (PAR4) antagonist. To continue on our development of novel anti-PAR4 agents, YD-3 was used as a lead compound and a series of its derivatives were synthesized and evaluated for their selective anti-PAR4 activity. Through structure-activity relationship (SAR) study, we identified the important functional groups contributing to anti-PAR4 activity, and these functional groups were kept intact during subsequent structural modification. Several new compounds with anti-PAR4 activity comparable to YD-3 were identified. Among them, ethyl 4-[1-(3-chlorobenzyl)-1H-indazol-3-yl]benzoate (33) showed the most potent inhibitory effect on PAR4-mediated platelet aggregation, ATP release, and P-selectin expression. On the other hand, ethyl 4-(1-phenyl-1H-indazol-3-yl)benzoate (83) exhibited dual inhibitory effects on PAR4 and thromboxane formation from arachidonic acid. The above findings can be used as guidelines for development of novel antiplatelet drug candidates.
- Chen, Hua-Sin,Kuo, Sheng-Chu,Teng, Che-Ming,Lee, Fang-Yu,Wang, Jih-Pyang,Lee, Yu-Chun,Kuo, Chiung-Wen,Huang, Ching-Che,Wu, Chin-Chung,Huang, Li-Jiau
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p. 1262 - 1278
(2008/09/17)
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- Pharmaceutical Compositions Comprising Nitrogen-Containing Fused Ring Coumpounds
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[Problems] The present invention provides pharmaceutical composition which is effective for the prophylaxis or treatment of pathology showing involvement of uric acid (hyperuricemia, gouty tophus, acute gout arthritis, chronic gout arthritis, gouty kidney, urolithiasis, renal function disorder, coronary arterial disease, ischemic heart disease and the like) and the like, and is superior in the time-course stability and dissolution property (disintegration property). [Solving Means] The pharmaceutical composition of the present invention is a pharmaceutical composition comprising a nitrogen-containing fused ring compound represented by the following formula [1] or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable additives, wherein the nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof is not in contact with a basic additive: wherein each symbol is as described in the specification.
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- Aspartic protease inhibitors via C1-homologation of peptidic aldehydes and studies on reduced amide isosteres
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(R)-Configured isophthalic hydroxyethylamines play an important role in the inhibition of β-secretase (BACE1). We present the synthesis of a number of (S)-configured hydroxyethylamine derivatives via 2-iodoethanol intermediates and the comparison with the
- Braun, Hannes A.,Zall, Andrea,Brockhaus, Manfred,Schütz, Marco,Meusinger, Reinhard,Schmidt, Boris
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p. 7990 - 7993
(2008/03/14)
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- Nitrogen-containing fused ring compounds and use thereof
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A URAT1 activity inhibitor containing a nitrogen-containing fused ring compound represented by the following formula [1]: wherein each symbol is as defined in the description. The present invention is useful for the prophylaxis or treatment of pathology showing involvement of uric acid, such as hyperuricemia, gouty tophus, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urolithiasis, renal function disorder, coronary artery disease, ischemic heart disease and the like.
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Page/Page column 94-95
(2010/11/25)
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- Short pseudopeptides containing turn scaffolds with high AT2 receptor affinity
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Two pentapeptides, Ac-Tyr-Ile-His-Pro-Phe/Ile, were synthesized and shown to have angiotensin II AT2 receptor affinity and agonistic activity. Based on these peptides, a new series of 13 pseudopeptides was synthesized via introduction of five d
- Georgsson, Jennie,Rosenstroem, Ulrika,Wallinder, Charlotta,Beaudry, Helene,Plouffe, Bianca,Lindeberg, Gunnar,Botros, Milad,Nyberg, Fred,Karlen, Anders,Gallo-Payet, Nicole,Hallberg, Anders
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p. 5963 - 5972
(2007/10/03)
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- NOVEL TRIAZOLOPYRIDINE COMPOUNDS
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This invention is directed generally to triazolopyridine compounds that generally inhibit p38 kinase, TNF, and/or cyclooxygenase activity. Such triazolopyridine include compounds generally corresponding in structure to the following formula (I): wherein R
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Page/Page column 65; 66
(2008/06/13)
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- Novel scaffolds for beta-helix mimicry
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Functionalized pyridazine derivatives having a low molecular weight and pharmaceutical compositions thereof are useful as alpha-helix mimetics and for treating conditions and/or disorders mediated by alpha-helix-binding receptors and proteins.
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Page/Page column 19
(2008/06/13)
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- COMPOUNDS WHICH INHIBIT BETA-SECRETASE ACTIVITY AND METHODS OF USE THEREOF
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The present invention provides novel beta-secretase inhibitors of the general formula (I), where the variables A1, A2, L1, L2, L3, R1, R2, R3, R4, R5, R6 and R7 are as defined in the claims, a method for their use in treating Alzheimer's disease, and methods for their use in reducing memapsin 2 catalytic activity.
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Page/Page column 59
(2008/06/13)
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- MACROCYCLIC LACTAMS AND PHARMACEUTICAL USE THEREOF
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The present invention relates to novel macrocyclic compounds of the formula (I) wherein R1, R2, R3, U, V, W, X, Y, Z and n are as defined in the specification, the number of ring atoms included in the macrocyclic ring being 14, 15, 16 or 17, in free base form or in acid addition salt form, to their preparation, to their use as pharmaceuticals and to pharma-ceutical compositions comprising them.
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Page/Page column 72
(2008/06/13)
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- Laser Flash Photolysis of tert-Butyl Aroylperbenzoates: Kinetics of the Singlet and Triplet States and the Aroylphenyl Radicals
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tert-Butyl aroylperbenzoates (1-4) were studied by laser flash photolysis (LFP). LFP (380 nm, pulse width ~350 fs) of 2 and 3 allowed direct observation of their singlet states, which showed broad absorption (λmax ~ 625 nm; τ ~ 20 and ~7.9 ps, respectively). The triplet state of each (λmax ~ 530-560 nm) rapidly dissociates by O-O cleavage as indicated by the short triplet lifetimes (e.g., triplet lifetime of 3 ~0.74 ns). The ~550 nm absorption obtained from the 355 nm LFP (pulse width ~7 ns) of 1, 2, and 4 has been assigned to the corresponding aroylphenyl radicals. Two representative radicals (4-benzoylphenyl 5 and 3-(4′-methylbenzoyl)phenyl 6) investigated in detail showed solvent-dependent lifetimes. Absolute bimolecular rate constants of reactions of these radicals with various quenchers including double-bond-containing monomers have been observed to range from 7.56 × 107 to 1.68 × 109 M-1 s-1 in CCl4 at room temperature. A possible structure of the aroylphenyl radicals and the transition responsible for the 550 nm absorption are discussed.
- Shah, Bipin K.,Neckers, Douglas C.
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p. 1830 - 1835
(2007/10/03)
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- Synthesis, Crystal Structures, and Laser Flash Photolysis of tert-Butyl Aroylperbenzoates
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tert-Butyl aroylperbenzoates (1-7) were synthesized. Single-crystal structures for 2 and 5 show that the perester and benzophenone carbonyl groups are almost coplanar in each. Laser flash photolysis (LFP, λex = 355 nm) of 1-5 in CCl4
- Shah, Bipin K.,Neckers, Douglas C.
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p. 8368 - 8372
(2007/10/03)
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- Pharmaceutical compositions comprising proton pump inhibitors and gastrin/cholecystokinin receptor ligands
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Pharmaceutical compositions comprising a proton pump inhibitor and a compound of the formula (I) or its pharmaceutically acceptable salts, are useful in treating gastrointestinal disorders. X and Y are independently ═N—, —N(R5)— (R5
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- Refinement and evaluation of a pharmacophore model for flavone derivatives binding to the benzodiazepine site of the GABAA receptor
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To further develop and evaluate a pharmacophore model previously proposed by Cook and co-workers (Drug Des. Discovery 1995, 12, 193-248) for ligands binding to the benzodiazepine site of the GABAA receptor, 40 new flavone derivatives have been synthesized and their affinities for the benzodiazepine site have been determined. Two new regions of steric repulsive interactions between ligand and receptor have been characterized, and the receptor region in the vicinity of 6- and 3′-substituents has been mapped out. 2′-Hydroxy substitution is shown to give a significant increase in affinity, which is interpreted in terms of a novel hydrogen bond interaction with the previously proposed hydrogen bond-accepting site A2. On the basis of the results of these studies and the refined pharmacophore model, 5′-bromo-2′-hydroxy-6-methylflavone, the highest affinity flavone derivative reported so far (Ki = 0.9 nM), was successfully designed. A comparison of the pharmacophore model with a recently proposed alternative model (Marder; et al. Bioorg. Med. Chem., 2001, 9, 323-335) has been made.
- Kahnberg, Pia,Lager, Erik,Rosenberg, Celia,Schougaard, Jette,Camet, Linda,Sterner, Olov,Nielsen, Elsebet ?stergaard,Nielsen, Mogens,Liljefors, Tommy
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p. 4188 - 4201
(2007/10/03)
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- Gastrin and cholecystokinin receptor ligands
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Compounds of formula (I) and their pharmaceutically acceptable salts are ligands at gastrin and/or cholecystokinin receptors. X and Y are independently ═N—, —N(R5)—═CH—, —S— or —O—. n is from 1 to 4; R1is H or C1to C1
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- 1,3-Disubstituted benzazepines as novel, potent, selective neuropeptide Y Y1 receptor antagonists
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A novel series of potent and selective non-peptide neuropeptide Y (NPY) Y1 receptor antagonists, having benzazepine nuclei, have been designed, synthesized, and evaluated for activity. Chemical modification of the R1 and R3 substitue
- Murakami, Yasushi,Hara, Hirokazu,Okada, Tetsuo,Hashizume, Hiroshi,Kii, Makoto,Ishihara, Yasunobu,Ishikawa, Michio,Shimamura, Mayumi,Mihara, Shin-Inchi,Kato, Goro,Hanasaki, Kohji,Hagishita, Sanji,Fujimoto, Masafumi
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p. 2621 - 2632
(2007/10/03)
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