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Structural Optimization of 4-Chlorobenzoylpiperidine Derivatives for the Development of Potent, Reversible, and Selective Monoacylglycerol Lipase (MAGL) Inhibitors
Monoacylglycerol lipase (MAGL) inhibitors are considered potential therapeutic agents for a variety of pathological conditions, including several types of cancer. Many MAGL inhibitors are reported in literature; however, most of them showed an irreversible mechanism of action, which caused important side effects. The use of reversible MAGL inhibitors has been only partially investigated so far, mainly because of the lack of compounds with good MAGL reversible inhibition properties. In this study, starting from the (4-(4-chlorobenzoyl)piperidin-1-yl)(4-methoxyphenyl)methanone (CL6a) lead compound that showed a reversible mechanism of MAGL inhibition (Ki = 8.6 μM), we started its structural optimization and we developed a new potent and selective MAGL inhibitor (17b, Ki = 0.65 μM). Furthermore, modeling studies suggested that the binding interactions of this compound replace a structural water molecule reproducing its H-bonds in the MAGL binding site, thus identifying a new key anchoring point for the development of new MAGL inhibitors.
Granchi, Carlotta,Rizzolio, Flavio,Palazzolo, Stefano,Carmignani, Sara,MacChia, Marco,Saccomanni, Giuseppe,Manera, Clementina,Martinelli, Adriano,Minutolo, Filippo,Tuccinardi, Tiziano
p. 10299 - 10314
(2016)
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Molecular iodine-catalyzed facile procedure for N-Boc protection of amines
An efficient and practical protocol for the protection of various structurally and electronically divergent aryl and aliphatic amines using (Boc)2O in the presence of a catalytic amount of molecular iodine (10 mol%) under solvent-free conditions at ambient temperature is presented.
Varala, Ravi,Nuvula, Sreelatha,Adapa, Srinivas R.
p. 8283 - 8286
(2006)
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2-Arylamino-6-ethynylpurines are cysteine-targeting irreversible inhibitors of Nek2 kinase
Renewed interest in covalent inhibitors of enzymes implicated in disease states has afforded several agents targeted at protein kinases of relevance to cancers. We now report the design, synthesis and biological evaluation of 6-ethynylpurines that act as covalent inhibitors of Nek2 by capturing a cysteine residue (Cys22) close to the catalytic domain of this protein kinase. Examination of the crystal structure of the non-covalent inhibitor 3-((6-cyclohexylmethoxy-7H-purin-2-yl)amino)benzamide in complex with Nek2 indicated that replacing the alkoxy with an ethynyl group places the terminus of the alkyne close to Cys22 and in a position compatible with the stereoelectronic requirements of a Michael addition. A series of 6-ethynylpurines was prepared and a structure activity relationship (SAR) established for inhibition of Nek2. 6-Ethynyl-N-phenyl-7H-purin-2-amine [IC50 0.15 μM (Nek2)] and 4-((6-ethynyl-7H-purin-2-yl)amino)benzenesulfonamide (IC50 0.14 μM) were selected for determination of the mode of inhibition of Nek2, which was shown to be time-dependent, not reversed by addition of ATP and negated by site directed mutagenesis of Cys22 to alanine. Replacement of the ethynyl group by ethyl or cyano abrogated activity. Variation of substituents on the N-phenyl moiety for 6-ethynylpurines gave further SAR data for Nek2 inhibition. The data showed little correlation of activity with the nature of the substituent, indicating that after sufficient initial competitive binding to Nek2 subsequent covalent modification of Cys22 occurs in all cases. A typical activity profile was that for 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide [IC50 0.06 μM (Nek2); GI50 (SKBR3) 2.2 μM] which exhibited >5-10-fold selectivity for Nek2 over other kinases; it also showed > 50% growth inhibition at 10 μM concentration against selected breast and leukaemia cell lines. X-ray crystallographic analysis confirmed that binding of the compound to the Nek2 ATP-binding site resulted in covalent modification of Cys22. Further studies confirmed that 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide has the attributes of a drug-like compound with good aqueous solubility, no inhibition of hERG at 25 μM and a good stability profile in human liver microsomes. It is concluded that 6-ethynylpurines are promising agents for cancer treatment by virtue of their selective inhibition of Nek2. This journal is
Bayliss, Richard,Boxall, Kathy,Carbain, Benoit,Coxon, Christopher R.,Fry, Andrew M.,Golding, Bernard T.,Griffin, Roger J.,Hardcastle, Ian R.,Harnor, Suzannah J.,Mas-Droux, Corine,Matheson, Christopher J.,Newell, David R.,Richards, Mark W.,Sivaprakasam, Mangaleswaran,Turner, David,Cano, Céline
supporting information
p. 707 - 731
(2020/08/24)

Carboxylation of Aryl Triflates with CO2 Merging Palladium and Visible-Light-Photoredox Catalysts
We report herein a visible-light-promoted, highly practical carboxylation of readily accessible aryl triflates at ambient temperature and a balloon pressure of CO2 by the combined use of palladium and photoredox Ir(III) catalysts. Strikingly, the stoichiometric metallic reductant is replaced by a nonmetallic amine reductant providing an environmentally benign carboxylation process. In addition, one-pot synthesis of a carboxylic acid directly from phenol and modification of estrone and concise synthesis of pharmaceutical drugs adapalene and bexarotene have been accomplished via late-stage carboxylation reaction. Furthermore, a parallel decarboxylation-carboxylation reaction has been demonstrated in an H-type closed vessel that is an interesting concept for the strategic sector. Spectroscopic and spectroelectrochemical studies indicated electron transfer from the Ir(III)/DIPEA combination to generate aryl carboxylate and Pd(0) for catalytic turnover.
Bhunia, Samir Kumar,Das, Pritha,Nandi, Shantanu,Jana, Ranjan
supporting information
p. 4632 - 4637
(2019/06/27)

AMINOPYRIDINE DERIVATIVES AS PHOSPHATIDYLINOSITOL PHOSPHATE KINASE INHIBITORS
The invention relates to inhibitors of PI5P4K inhibitors useful in the treatment of cancers, neurodegenerative diseases, inflammatory disorders, and metabolic diseases, having the Formula: (I) where A, B, R1, X1, X2, and W are described herein.
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Paragraph 0634

(2019/07/13)

Design and synthesis of selective CYP1B1 inhibitor via dearomatization of α-naphthoflavone
Selective cytochrome P450 (CYP) 1B1 inhibition has potential as an anticancer strategy that is unrepresented in the current clinical arena. For development of a selective inhibitor, we focused on the complexity caused by sp3-hybridized carbons and synthesized a series of benzo[h]chromone derivatives linked to a non-aromatic B-ring using α-naphthoflavone (ANF) as the lead compound. Ring structure comparison suggested compound 37 as a suitable cyclohexyl-core with improved solubility. Structural evolution of 37 produced the azide-containing cis-49a, which had good properties in three important respects: (1) selectivity for CYP1B1 over CYP1A1 and CYP1A2 (120-times and 150-times, respectively), (2) greater inhibitory potency of >2 times that of ANF, and (3) improved solubility. The corresponding aromatic B-ring compound 59a showed low selectivity and poor solubility. To elucidate the binding mode, we performed X-ray crystal structure analysis, which revealed the interaction mode and explained the subtype selectivity of cis-49a.
Kubo, Makoto,Yamamoto, Keiko,Itoh, Toshimasa
p. 285 - 304
(2019/01/04)

Comprehensive Synthesis of Amino Acid-Derived Thiazole Peptidomimetic Analogues to Understand the Enigmatic Drug/Substrate-Binding Site of P-Glycoprotein
A novel set of 64 analogues based on our lead compound 1 was designed and synthesized with an initial objective of understanding the structural requirements of ligands binding to a highly perplexing substrate-binding site of P-glycoprotein (P-gp) and their effect on modulating the ATPase function of the efflux pump. Compound 1, a stimulator of P-gp ATPase activity, was transformed to ATPase inhibitory compounds 39, 53, and 109. The ATPase inhibition by these compounds was predominantly contributed by the presence of a cyclohexyl group in lieu of the 2-aminobenzophenone moiety of 1. The 4,4-difluorocyclohexyl analogues, 53 and 109, inhibited the photolabeling by [125I]-IAAP, with IC50 values of 0.1 and 0.76 μM, respectively. Selected compounds were shown to reverse paclitaxel resistance in HEK293 cells overexpressing P-gp and were selective toward P-gp over CYP3A4. Induced-fit docking highlighted a plausible binding pattern of inhibitory compounds in the putative-binding pocket of P-gp. The current study underscores the stringent requirement by P-gp to bind to chemically similar molecules.
Patel, Bhargav A.,Abel, Biebele,Barbuti, Anna Maria,Velagapudi, Uday Kiran,Chen, Zhe-Sheng,Ambudkar, Suresh V.,Talele, Tanaji T.
p. 834 - 864
(2018/02/17)

Carboxylation of Aromatic and Aliphatic Bromides and Triflates with CO2 by Dual Visible-Light–Nickel Catalysis
We report the efficient carboxylation of bromides and triflates with K2CO3 as the source of CO2 in the presence of an organic photocatalyst in combination with a nickel complex under visible light irradiation at room temperature. The reaction is compatible with a variety of functional groups and has been successfully applied to the synthesis and derivatization of biologically active molecules. In particular, the carboxylation of unactivated cyclic alkyl bromides proceeded well with our protocol, thus extending the scope of this transformation. Spectroscopic and spectroelectrochemical investigations indicated the generation of a Ni0 species as a catalytic reactive intermediate.
Meng, Qing-Yuan,Wang, Shun,K?nig, Burkhard
supporting information
p. 13426 - 13430
(2017/10/07)

KINASE INHIBITORS
Compounds that inhibit kinase Lck or Btk, pharmaceutically acceptable salts, hydrides, stereoisomers and pharmaceutical compositions thereof are disclosed.
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Paragraph 0129; 0130

(2017/10/07)

Structure-Based Discovery of Novel and Selective 5-Hydroxytryptamine 2B Receptor Antagonists for the Treatment of Irritable Bowel Syndrome
Here we employed structure-based ligand discovery techniques to explore a recently determined crystal structure of the 5-hydroxytryptamine 2B (5-HT2B) receptor. Ten compounds containing a novel chemical scaffold were identified; among them, seven molecules were active in cellular function assays with the most potent one exhibiting an IC50 value of 27.3 nM. We then systematically probed the binding characteristics of this scaffold by designing, synthesizing, and testing a series of structural modifications. The structure-activity relationship studies strongly support our predicted binding model. The binding profiling across a panel of 11 5-HT receptors indicated that these compounds are highly selective for the 5-HT2B receptor. Oral administration of compound 15 (30 mg/kg) produced significant attenuation of visceral hypersensitivity in a rat model of irritable bowel syndrome (IBS). We expect this novel scaffold will serve as the foundation for the development of 5-HT2B antagonists for the treatment of IBS.
Zhou, Yu,Ma, Jing,Lin, Xingyu,Huang, Xi-Ping,Wu, Kaichun,Huang, Niu
p. 707 - 720
(2016/02/09)

Total Synthesis of cis-Clavicipitic Acid from Asparagine via Ir-Catalyzed C-H bond Activation as a Key Step
4-Substituted tryptophan derivatives and the total synthesis of cis-clavicipitic acid were achieved in reactions in which Ir-catalyzed C-H bond activation was a key step. The starting material for these reactions is asparagine, which is a cheap natural amino acid. The reductive amination step from the 4-substituted tryptophan derivative gave cis-clavicipitic acid with perfect diastereoselectivity.
Tahara, Yu-Ki,Ito, Mamoru,Kanyiva, Kyalo Stephen,Shibata, Takanori
supporting information
p. 11340 - 11343
(2015/08/03)

5-HT2B ANTAGONISTS
The invention provides novel compounds and compositions comprising a 5-HT2B antagonist of formula I and related methods for treating a person having a disorder characterized by undesirable 5-HT2B receptor signaling, such as migraine, irritable bowel syndrome (IBS), pulmonary arterial hypertension (PAH), fibrosis, hepatocellular cancer, a small intestinal neuroendocrine tumor, cardiovascular disorders, and gastrointestinal (GI) tract disorders.
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Paragraph 073; 074

(2015/11/09)

HETEROCYCLYL COMPOUNDS AS MEK INHIBITORS
The present disclosure is related to heteroaryl compounds as MEK inhibitors. These compounds include heteroaryl compounds of formula I, their pharmaceutically acceptable salts, combinations with suitable medicament and pharmaceutical compositions thereof.
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Paragraph 0215-0216

(2015/05/26)

MONOMERS CAPABLE OF DIMERIZING IN AN AQUEOUS SOLUTION, AND METHODS OF USING SAME
Described herein are monomers capable of forming a biologically useful multimer when in contact with one, two, three or more other monomers in an aqueous media. In one aspect, such monomers may be capable of binding to another monomer in an aqueous media (e.g. in vivo) to form a multimer, (e.g. a dimer). Contemplated monomers may include a ligand moiety, a linker element, and a connector element that joins the ligand moiety and the linker element. In an aqueous media, such contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecules substantially simultaneously, e.g., modulate two or more binding domains on a protein or on different proteins.
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Paragraph 0500; 0507-0508

(2014/07/22)

Study of the nano-morphological versatility by self-assembly of a peptide mimetic molecule in response to physical and chemical stimuli
A small peptide mimetic molecule can form diverse nanostructures such as nano-vesicles, nano-tubes and nano-ribbons/fibrils by self-assembly, in response to various physical and chemical stimulations. The Royal Society of Chemistry 2014.
Kar, Sudeshna,Wu, Kung-Wei,Hsu, I-Jui,Lee, Chi-Rung,Tai, Yian
supporting information
p. 2638 - 2641
(2014/03/21)

Design, synthesis and biological evaluation of 4′-demethyl-4-deoxypodophyllotoxin derivatives as novel tubulin and histone deacetylase dual inhibitors
A new class of 4′-demethyl-4-deoxypodophyllotoxin derivatives has been designed and synthesized as tubulin-HDAC dual inhibitors. Biological evaluation of these hybrids included the inhibitory activity of HDAC, in vitro cell cycle analysis in HCT-116 cells as well as cytotoxicity against two cancer cell lines (A549 and HCT116). The distance and angle between the HDAC capping group and the zinc binding group were systematically varied. Compounds 14a and 14c showed most potent dual inhibitory activity and powerful antiproliferative activity on HCT116 and A549 cell lines. This journal is
Zhang, Xuan,Zhang, Jie,Su, Mingbo,Zhou, Yubo,Chen, Yi,Li, Jia,Lu, Wei
p. 40444 - 40448
(2014/12/11)

Synthesis and biological evaluation of glucagon-like peptide-1 receptor agonists
In this study, a series of fused-heterocyclic derivatives were systematically designed and synthesized using an efficient route, and evaluated in terms of GLP-1R agonist activity. We employed short synthetic steps and reactions that are tolerant of the presence of various functional groups and suitable for parallel operations to enable the rapid generation of libraries of diverse and structurally complex small molecules. Of the compounds synthesized, 3-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a] pyridin-2-yl)phenyl methanesulfonate (8e) was the most potent agonist with an EC50 of 7.89 μM, and thus is the compound with the greatest potential for application. These findings represent a valuable starting point for the design and discovery of small-molecule GLP-1R agonists that can be administered orally.
Zhang, Yu-Juan,Shen, Liu-Lan,Cheon, Hyae-Gyeong,Xu, Yong-Nan,Jeong, Jin-Hyun
p. 588 - 599
(2014/06/09)

PRMT5 INHIBITORS AND USES THEREOF
Described herein are compounds of formula (A), pharmaceutically acceptable salts thereof, and pharmaceutical com-positions thereof. Compounds of the present invention are useful for inhibiting PRMT5 activity. Methods of using the compounds for treating PRMT5-mediated disorders are also described.
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Paragraph 00331

(2014/07/08)

Synthesis and biological activities of novel pleuromutilin derivatives with a substituted thiadiazole moiety as potent drug-resistant bacteria inhibitors
A series of novel pleuromutilin derivatives possessing thiadiazole moieties were synthesized via acylation reactions under mild conditions. The in vitro antibacterial activities of the derivatives against methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Escherichia coli, and Streptococcus agalactiae were tested by the agar dilution method and Oxford cup assay. The majority of the tested compounds displayed moderate antibacterial activities. Importantly, the three compounds with amino or tertiary amine groups in their side chains, 11, 13b, and 15c, were the most active antibacterial agents. Docking experiments carried out on the peptidyl transferase center (PTC) of 23S rRNA proved that there is a reasonable direct correlation between the binding free energy (ΔGb, kcal/mol) and the antibacterial activity. Moreover, the pharmacokinetic profiles of 11 and 15c in rat were characterized by moderate clearance and oral bioavailability.
Shang, Ruofeng,Pu, Xiuying,Xu, Ximing,Xin, Zhijun,Zhang, Chao,Guo, Wenzhu,Liu, Yu,Liang, Jianping
p. 5664 - 5678
(2014/08/05)

Synthesis and antibacterial evaluation of novel pleuromutilin derivatives
A series of novel pleuromutilin derivatives possessing thioether moiety has been synthesized via acylation reaction under mild conditions. Their in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Escherichia coli, and Streptococcus agalactiae were tested by agar dilution method and Oxford cup assay. Among the 17 compounds screened, 14-O-[(4-methoxybenzamide-2- methylpropane-2-yl) thioacetate] mutilin 4i, 14-O-[(2-aminobenzamide-2- methylpropane-2-yl) thioacetate] mutilin 5a and 14-O-[(4-aminobenzamide-2- methylpropane-2-yl) thioacetate] mutilin 5c were resulted as most active antibacterial agents.
Shang, Ruofeng,Liu, Yu,Xin, Zhijun,Guo, Wenzhu,Guo, Zhiting,Hao, Baocheng,Jianping, Liang
p. 231 - 238
(2013/07/27)

Active ion transporters from readily accessible acyclic octapeptides containing 3-aminobenzoic acid and alanine
Ion transporters have been developed from acyclic octapeptides comprising l/d alanine and m-aminobenzoic acid. These octapeptides transport cations up to 3 times faster than their cyclic analog through lipid vesicles. Preliminary CD, XRD and computational
Benke, Bahiru P.,Madhavan, Nandita
supporting information
p. 7340 - 7342
(2013/09/23)

γ-Amino butyric acid analogs as novel potent GABA-AT inhibitors: Molecular docking, synthesis, and biological evaluation
A new series, of γ-amino butyric acid analogs were designed and synthesized as novel potent GABA-AT inhibitors. A structure-activity relationship study was performed by correlating the effect of different substituents with GABA-AT inhibitory activity of the title compounds. The preliminary bioassays showed that acid hydrazones exhibited excellent inhibitory activities in micromolar (0.07-0.56 μM) range, while Schiff's bases showed variable results. The most potent compound, 4-amino-N'-[(1Z)-1-(2-bromophenyl) ethylidene]butanehydrazide (AHG177) showed inhibitory potency (IC50) of 0.073 μM. Aminobutyrate transaminase is a pyridoxal-P enzyme which follows a bi-bi ping pong mechanism and in pyridoxamine form can readily transaminate only with succinic semialdehyde and 2-oxoglutarate. The results strongly suggest that only the pyridoxal form of the enzyme is capable of reacting with the ligands. Our findings open up the possibility to extend this protocol to different databases in order to find new potential inhibitor for promising targets based on a rational drug design process.
Bansal,Sinha,Khosa
p. 134 - 146
(2013/03/13)

Identification of vitamin D3-based hedgehog pathway inhibitors that incorporate an aromatic A-ring isostere
Previous structure-activity relationship studies for vitamin D3 (VD3) inhibition of Hedgehog (Hh) signaling directed the design, synthesis, and evaluation of a series of VD3-based analogues that contain an aromatic A-ring mimic. Characterization of these
Deberardinis, Albert M.,Banerjee, Upasana,Hadden, M. Kyle
p. 590 - 595
(2013/07/26)

HETEROCYCLYL COMPOUNDS AS MEK INHIBITORS
The present disclosure is related to heteroaryl compounds as MEK inhibitors. These compounds include heteroaryl compounds of Formula (I), their pharmaceutically acceptable salts, combinations with suitable medicament and pharmaceutical compositions thereo
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Page/Page column 43

(2013/09/26)

Synthesis of benzoic acids and polybenzamides containing tertiary alkylamino functionality
The high-yielding and easily scalable synthesis of a number of benzoic acids bearing a tertiary alkylamino functionality has been achieved. The flexible synthesis began from readily available aminobenzoic acids or terephthaloyl chloride and requires almost no chromatography. Coupling of the synthesised amino acids to a range of substituted anilines was achieved when utilizing a specific combination of DIC, HOBt and DMAP.
Khan, Gul Shahzada,Dickson, Benjamin D.,Barker, David
experimental part
p. 1790 - 1801
(2012/03/11)

Supramolecular double helix from capped γ-peptide
The single crystal X-ray diffraction study of capped γ-peptide reveal that the peptide adopts helical conformation which self-assemble to form a supramolecular parallel double helical structure using intermolecular hydrogen bonding as well as π-π stacking
Maity, Suman Kumar,Maity, Sibaprasad,Jana, Poulami,Haldar, Debasish
supporting information; experimental part
p. 711 - 713
(2012/02/01)

Novel Compounds for the Treatment of Diseases Associated with Amyloid or Amyloid-Like Proteins
The present invention relates to novel compounds that can be employed in the treatment of a group of disorders and abnormalities associated with amyloid protein, such as Alzheimer's disease, and of diseases or conditions associated with amyloid-like proteins. The compounds of the present invention can also be used in the treatment of ocular diseases associated with pathological abnormalities/changes in the tissues of the visual system. The present invention further relates to pharmaceutical compositions comprising these compounds and to the use of these compounds for the preparation of medicaments for treating or preventing diseases or conditions associated with amyloid and/or amyloid-like proteins. A method of treating or preventing diseases or conditions associated with amyloid and/or amyloid-like proteins is also disclosed.
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Page/Page column 53

(2011/11/30)

Design, synthesis and evaluation of N-benzoylindazole derivatives and analogues as inhibitors of human neutrophil elastase
Human neutrophil elastase (HNE) plays an important role in tumour invasion and inflammation. A series of N-benzoylindazoles was synthesized and evaluated for their ability to inhibit HNE. We found that this scaffold is appropriate for HNE inhibitors and that the benzoyl fragment at position 1 is essential for activity. The most active compounds inhibited HNE activity with IC50 values in the submicromolar range. Furthermore, docking studies indicated that the geometry of an inhibitor within the binding site and energetics of Michaelis complex formation were key factors influencing the inhibitor's biological activity. Thus, N-benzoylindazole derivatives and their analogs represent novel structural templates that can be utilized for further development of efficacious HNE inhibitors.
Crocetti, Letizia,Giovannoni, Maria Paola,Schepetkin, Igor A.,Quinn, Mark T.,Khlebnikov, Andrei I.,Cilibrizzi, Agostino,Piaz, Vittorio Dal,Graziano, Alessia,Vergelli, Claudia
scheme or table
p. 4460 - 4472
(2011/09/12)

Water soluble multi-biotin-containing compounds
Water-soluble discrete multi-biotin-containing compounds with at least three (3) biotin moieties are disclosed. The water-soluble biotin-containing compounds may additionally comprise one or more moieties that confer resistance to cleavage by biotinidase or that is cleavable in vitro or in vivo. The discrete multi-biotin-containing compounds may include a reactive moiety that provides a site for reaction with yet another moiety, such as a targeting, diagnostic or therapeutic functional moiety. Biotinylation reagents comprising water-soluble linker moieties are also disclosed and may additionally comprise a biotinidase protective group. Methods for amplifying the number of sites for binding biotin-binding proteins at a selected target using multi-biotin compounds also are disclosed.
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Page/Page column 65

(2010/11/24)

Anion transport in liposomes responds to variations in the anchor chains and the fourth amino acid of heptapeptide ion channels
Seven heptapeptide derivatives have been prepared. The peptide structure is (Gly)3Xxx(Gly)3 in which Xxx stands for a variable amino acid. The amino acid variations include azetidine carboxylic acid, pipecolic acid, meta-aminobenzoic
Ferdani, Riccardo,Pajewski, Robert,Djedovic, Natasha,Pajewska, Jolanta,Schlesinger, Paul H.,Gokel, George W.
p. 673 - 680
(2007/10/03)

NEW COMPOUNDS
The present invention relates to new compounds of formula I, (I) a process for their preparation and new intermediates prepared therein, pharmaceutical formulations containing said compounds and to the use of said compounds in therapy.
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Page 137-138

(2010/02/06)

Non-peptidic cyclophilin binding compounds and their use
The invention relates to non-peptidic compounds that possess bioactive properties, such as the ability to protect neuronal cells from otherwise lethal treatments or the ability to promote the growth or regeneration of neuronal cells. In part, the inventio
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(2008/06/13)

A Lewis acid-mediated protocol for the protection of aryl amines as their Boc-derivatives
A new protocol of protection of poorly reactive aryl amines and functionalized amines with Boc2O in the presence of Zn(ClO 4)2·6H2O as the catalyst is reported. The catalytic action of Zn(ClO4)2·6H2O is specific for the activation of the pyrocarbonates, thus acid sensitive functionalities and stereochemical configurations of the starting materials remain unaltered in the protection process.
Bartoli, Giuseppe,Bosco, Marcella,Locatelli, Manuela,Marcantoni, Enrico,Massaccesi, Massimo,Melchiorre, Paolo,Sambri, Letizia
p. 1794 - 1798
(2007/10/03)

INHIBITORS OF ALPHA-4 BETA-1 MEDIATED CELL ADHESION
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Page 34

(2010/02/05)

Cyclopentyl sulfonamide derivatives
The present invention provides certain cyclopentyl sulfonamide derivatives of formula (I): useful for potentiating glutamate receptor function in a mammal. It also relates to novel cyclopentyl sulfonamide derivatives, to processes for their preparation and to pharmaceutical compositions containing them.
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Page/Page column 37

(2010/01/31)

Non-peptidic cyclophilin binding compounds and their use
The invention relates to non-peptidic compounds that possess bioactive properties, such as the ability to protect neuronal cells from otherwise lethal treatments or the ability to promote the growth or regeneration of neuronal cells. In part, the inventio
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Page 11

(2010/02/06)

Non-peptidic cyclophilin binding compounds and their use
This invention relates to pharmaceutical compositions and methods of using non-peptidic cyclophilin-binding compounds in medical conditions involving breakdown of mitochondrial energy metabolism induced by calcium overload, in treating alopecia and promot
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(2008/06/13)

Design, synthesis, and biological evaluation of a series of lavendustin A analogues that inhibit EGFR and Syk tyrosine kinases, as well as tubulin polymerization
A series of N-alkylamide analogues of the lavendustin A pharmacophore were synthesized and tested for inhibitiofi of the epidermal growth factor receptor (EGFR) protein tyrosine kinase and the nonreceptor protein tyrosine kinase Syk. Although several comp
Mu,Coffing,Riese II,Geahlen,Verdier-Pinard,Hamel,Johnson,Cushman
p. 441 - 452
(2007/10/03)

Development of potent and selective plasmin and plasma kallikrein inhibitors and studies on the structure-activity relationship
Based on structure-activity relationship studies, we designed and synthesized plasmin (PL) and plasma kallikrein (PK) inhibitors. Trans-(4-aminomethylcyclohexanecarbonyl)-Tyr(O-PIC)-octylamide inhibited PL, PK, urokinase (UK) and thrombin (TH) with IC50 values of 0.53, 30, 5.3 and >400 μM, respectively. Trans-(4-aminomethylcyclohexanecarbonyl)-Tyr(O-2-Pyrim)-4-carboxyanilide inhibited PL, PK, UK and TH with IC50 values of 36, 0.56, 440 and >1000 μM, respectively.
Okada, Yoshio,Tsuda, Yuko,Tada, Mayako,Wanaka, Keiko,Okamoto, Utako,Hijikata-Okunomiya, Akiko,Okamoto, Shosuke
p. 1964 - 1972
(2007/10/03)

Toward the antibody-catalyzed chemiluminescence. Design and synthesis of hapten
Hapten 4 was synthesized to generate catalytic antibodies triggering chemiluminescence by catalyzing the decomposition of the 1,2-dioxetane 3. The hapten 4 was so designed as to elicit a negatively charged functional group in the antibody combining site to catalyze the β-elimination of the protecting group in 3 as well as to lock the protecting group into an energetically favorable anti-periplanar conformation.
Sawa, Masaaki,Imaeda, Yasuhiro,Hiratake, Jun,Fujii, Ryota,Umeshita, Ritsuko,Watanabe, Mitsuo,Kondo, Hitoshi,Oda, Jun'ichi
p. 647 - 652
(2007/10/03)

Process of preparing benzodiazepine compounds useful as antagonists of CCK or of gastrine
A benzodiazepine derivative of formula I, or a pharmaceutically acceptable salt thereof: STR1 wherein: (a) R4 is an alkyl, cycloalkyl or aryl group. (b) R10 is chosen from halo, OH, CH3, OCH3, NR11 R12, NO2, NHCHO, CO2 H and CN, and R11 and R12 are independently selected from H and alkyl (C1 -C5) or together NR11 R12 form a cyclic structure II, STR2 wherein a is 1-6; and (c) R2 is an aromatic 5- or 6-membered, substituted or unsubstituted heterocycle containing at least two heteroatoms of which at least one is nitrogen. These compounds are gastrin and/or CCK-B receptor antagonists.
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(2008/06/13)

(3R)-N-(1-(tert-butylcarbonylmethyl)-2,3-dihydro-2-oxo-5-(2-pyridyl)- 1H-1,4-benzodiazepin-3-yl)-N'-(3-(methylamino)phenyl)urea (YF476): A potent and orally active gastrin/CCK-B antagonist
A number of new 1,4-benzodiazepin-2-one-based gastrin/CCK-B receptor antagonists related to the archetypal analogue L-365,260, and more closely to the recently reported compound YM022, have been synthesized and evaluated for biological activity. The compounds were screened for their ability to inhibit the binding of [125I]CCK-8 to gastrin/CCK-B receptors prepared from rat brains and that of [3H]L-364,718 to CCK-A receptors from rat pancreas, and were shown to be potent and selective ligands for the gastrin/CCK-B receptor. Functional studies in vivo demonstrated the compounds to be antagonists of the receptor as evidenced by their ability to inhibit pentagastrin-induced gastric acid secretion in anesthetized rats. More extensive evaluation in viva included determination of ED50 values in the rat acid secretion model for selected compounds and an examination of the effect of these compounds on pentagastrin-induced gastric acid secretion in Heidenhain pouch dogs following oral and intravenous administration. Two compounds, i.e. (3R)-N- [1-[(tert-butylcarbonyl)methyl]-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4- benzodiazepin-3-yl]-N'-[3-(methylamino)phenyl]urea, 15c (YF476), and (3R)-N- [1-[(tert-Butylcarbonyl)methyl]-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4- benzodiazepin-3-yl]-N'-[3-(dimethylamino)phenyl]urea hydrochloride, 15d, showed potent dose-dependent effects in both models with the former showing excellent oral bioavailability and an ED50 of 21 nmol/kg po in dogs. 15e is currently under clinical investigation for the treatment of gastro-oesophagal reflux disease (GORD).
Semple, Graeme,Ryder, Hamish,Rooker, David P.,Batt, Andrzej R.,Kendrick, David A.,Szelke, Michael,Ohta, Mitsuaki,Satoh, Masato,Nishida, Akito,Akuzawa, Shinobu,Miyata, Keiji
p. 331 - 341
(2007/10/03)

Structure-activity relationships of a series of substituted benzamides: Potent D2/5-HT2 antagonists and 5-HT1a agonists as neuroleptic agents
A series of substituted (4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)benzamide derivatives was prepared and evaluated as potential atypical antipsychotic agents. The target compounds were readily prepared from their benzoyl chloride, benzoic acid, or isatoic anhydride precursors, and they were evaluated in vitro for their ability to bind to dopamine D2, serotonin 5-HT2, and serotonin 5-HT1a receptors. To assess the potential antipsychotic activity of these compounds, we investigated their ability to inhibit the apomorphine-induced climbing response in mice. Selected compounds were evaluated further to determine their side-effect potentials. Structure-activity relationships of both mono- and polysubstituted benzamides are discussed herein. While several analogues had potent in vitro and in vivo activities indicative of potential atypical antipsychotic activity, anthranilamide 77 (1192U90) demonstrated a superior pharmacological profile. As a result of this investigation, 1192U90 (2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)benzamide hydrochloride) was selected for further evaluation and is currently in phase I clinical trials as a potential atypical antipsychotic agent.
Norman, Mark H.,Rigdon, Greg C.,Hall, William R.,Navas III, Frank
p. 1172 - 1188
(2007/10/03)

Synthesis and Structure-Activity Studies of a Series of salicylates as Inhibitors of EGF Receptor-Associated Tyrosine Kinase Activity
The synthesis and structure-activity relationships of a series of salicylates and a series of salicylates as inhibitors of EGF receptor-associated tyrosine kinase activity are described.Their inhibitory potency was evaluated in vitro using ER 22 cell membranes (CCL 39 cells transfected with EGF receptor) as an enzyme source and the tridecapeptide RRSrc (RRLIEDAEYAARG) as substrate.Their cellular activity was measured by inhibition of the EGF-stimulated DNA synthesis of ER 22 cells.Chemical modifications were made to analyze the role of the different substituents.The amino series was found to be more active than the imino series.The hydroquinone moiety appears to be essential for tyrosine kinase inhibitory activity in the series of 5-salicylates.Comparison of the imino and amino series by molecular modeling techniques provides further evidence in support of the hypothesis that the important reduced linking chain, CH2NH allows the correct positioning of the 2,5-dihydroxybenzyl ring, possibly in a cis-like conformational arrangement.
Chen, Huixiong,Boiziau, Janine,Parker, Fabienne,Maroun, Rachid,Tocque, Bruno,et al.
p. 4094 - 4098
(2007/10/02)

N-substituted mercaptopropanamide derivatives
Novel N-substituted mercaptopropanamide derivatives of the formula: STR1 wherein R1 is mercapto or a group convertible into mercapto when cleaved within the biobody, W is hydrogen atom, an alkyl or an aralkyl, R2 is an aryl which may optionally have substituent(s), a heterocyclic group which may optionally have substituent(s), or an alkyl which may optionally have substituent(s), X is a cycloalkylene, a cycloalkylidene, or a phenylene which may optionally have substituent(s) or may optionally be fused with other ring, and R3 is carboxyl or a group convertible into carboxyl when cleaved within the biobody, or a pharmaceutically acceptable salt thereof, and a solid solution of said N-substituted mercaptopropanamide derivative with an amino acid, which have excellent enkephalinase inhibitory activity and are useful for the treatment of mild to moderate pain, and a pharmaceutical composition containing said compounds as an active ingredient, and processes for preparing these compounds.
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(2008/06/13)

N-substituted mercaptopropanamide derivatives
Novel N-substituted mercaptopropanamide derivatives of the formula: STR1 wherein R1 is mercapto or a group convertible into mercapto when cleaved within the biobody, W is hydrogen atom, an alkyl or an aralkyl, R2 is an aryl which may optionally have substituent(s), a heterocyclic group which may optionally have substituent(s), or an alkyl which may optionally have substituent(s), X is a cycloalkylene, a cycloalkylidene, or a phenylene which may optionally have substituent(s) or may optionally be fused with other ring, and R3 is carboxyl or a group convertible into carboxyl when cleaved within the biobody, or a pharmaceutically acceptable salt thereof, and a solid solution of said N-substituted mercaptopropanamide derivative with an amino acid, which have excellent enkephalinase inhibitory activity and are useful for the treatment of mild to moderate pain, and a pharmaceutical composition containing said compounds as an active ingredient, and processes for preparing these compounds.
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(2008/06/13)

Analogs of Ac-CCK-7 Incorporating Dipeptide Mimics in Place of Met28-Gly29
A series of analogs of Ac-CCK-7 28-Gly29-Trp-Met-Asp-Phe-NH2, (1)> were prepared in which The Met28-Gly29 dipeptide was replaced by ω-aminoalkanoic acids.Compounds were assessed in binding assay
Tilley, Jefferson W.,Danho, Waleed,Shiuey, Shian-Jun,Kulesha, Irina,Swistok, Joseph,et al.
p. 3774 - 3783
(2007/10/02)

Mercapto-acylamino acids as antihypertensives
Novel mercapto-acylamino acids useful as analgesic, as well as in the treatment of hypertension and congestive heart failure and combinations of mercapto acylamino acids and atrial natriuretic factors or angiotensin converting enzyme inhibitors useful for
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(2008/06/13)