- Identification of BR102910 as a selective fibroblast activation protein (FAP) inhibitor
-
Fibroblast activation protein (FAP) belongs to the family of prolyl-specific serine proteases and displays both exopeptidase and endopeptidase activities. FAP expression is undetectable in most normal adult tissues, but is greatly upregulated in sites of tissue remodeling, which include fibrosis, inflammation and cancer. Due to its restricted expression pattern and dual enzymatic activities, FAP inhibition is investigated as a therapeutic option for several diseases. In the present study, we described the structure–activity relationship of several synthesized compounds against DPPIV and prolyl oligopeptidase (PREP). In particular, BR102910 (compound 24) showed nanomolar potency and high selectivity. Moreover, the in vivo FAP inhibition study of BR102910 (compound 24) using C57BL/6J mice demonstrated exceptional profiles and satisfactory FAP inhibition efficacy. Based on excellent in vitro and in vivo profiles, the potential of BR102910 (compound 24) as a lead candidate for the treatment of type 2 diabetes is considered.
- Jung, Hui Jin,Nam, Eun Hye,Park, Jin Young,Ghosh, Prithwish,Kim, In Su
-
supporting information
(2021/02/26)
-
- A Diverse Library of Chiral Cyclopropane Scaffolds via Chemoenzymatic Assembly and Diversification of Cyclopropyl Ketones
-
Chiral cyclopropane rings are key pharmacophores in pharmaceuticals and bioactive natural products, making libraries of these building blocks a valuable resource for drug discovery and development campaigns. Here, we report the development of a chemoenzymatic strategy for the stereoselective assembly and structural diversification of cyclopropyl ketones, a highly versatile yet underexploited class of functionalized cyclopropanes. An engineered variant of sperm whale myoglobin is shown to enable the highly diastereo- and enantioselective construction of these molecules via olefin cyclopropanation in the presence of a diazoketone carbene donor reagent. This biocatalyst offers a remarkably broad substrate scope, catalyzing this reaction with high stereoselectivity across a variety of vinylarene substrates as well as a range of different α-aryl and α-alkyl diazoketone derivatives. Chemical transformation of these enzymatic products enables further diversification of these molecules to yield a collection of structurally diverse cyclopropane-containing scaffolds in enantiopure form, including core motifs found in drugs and natural products as well as novel structures. This work illustrates the power of combining abiological biocatalysis with chemoenzymatic synthesis for generating collections of optically active scaffolds of high value for medicinal chemistry and drug discovery.
- Nam, Donggeon,Steck, Viktoria,Potenzino, Robert J.,Fasan, Rudi
-
p. 2221 - 2231
(2021/02/16)
-
- N-Alkenylation of hydroxamic acid derivatives with ethynyl benziodoxolone to synthesizecis-enamides through vinyl benziodoxolones
-
The stereoselective synthesis ofcis-β-N-alkoxyamidevinyl benziodoxolones (cis-β-N-RO-amide-VBXs) fromO-alkyl hydroxamic acids in the presence of an ethynyl benziodoxolone-acetonitrile complex (EBX-MeCN) is reported herein. The reaction was performed under mild conditions including an aqueous solvent, a mild base, and room temperature. The reaction tolerated variousO-alkyl hydroxamic acids derived from carboxylic acids, such as amino acids, pharmaceuticals, and natural products. Vinyl dideuteratedcis-β-N-MeO-amide-VBXs were also synthesized using deuterium oxide as the deuterium source. Valine-derivedcis-β-N-MeO-amide-VBX was stereospecifically derivatized to hydroxamic acid-derivedcis-enamides without the loss of stereoselectivity or reduction in the deuterium/hydrogen ratio.
- Shimbo, Daisuke,Maruyama, Toshifumi,Tada, Norihiro,Itoh, Akichika
-
supporting information
p. 2442 - 2447
(2021/04/02)
-
- N-monoarylacetothioureas as potent urease inhibitors: synthesis, SAR, and biological evaluation
-
A urease inhibitor with good in vivo profile is considered as an alternative agent for treating infections caused by urease-producing bacteria such as Helicobacter pylori. Here, we report a series of N-monosubstituted thioureas, which act as effective urease inhibitors with very low cytotoxicity. One compound (b19) was evaluated in detail and shows promising features for further development as an agent to treat H. pylori caused diseases. Excellent values for the inhibition of b19 against both extracted urease and urease in intact cell were observed, which shows IC50 values of 0.16 ± 0.05 and 3.86 ± 0.10 μM, being 170- and 44-fold more potent than the clinically used drug AHA, respectively. Docking simulations suggested that the monosubstituted thiourea moiety penetrates urea binding site. In addition, b19 is a rapid and reversible urease inhibitor, and displays nM affinity to urease with very slow dissociation (koff=1.60 × 10?3 s?1) from the catalytic domain.
- Fang, Hai-Lian,He, Jie-Ling,Li, Wei-Yi,Liu, Shan-Shan,Ni, Wei-Wei,Pan, Xing-Ming,Xiao, Zhu-Ping,Ye, Ya-Xi,Yi, Juan,Zhou, Mi,Zhou, Tian-Li,Zhu, Hai-Liang
-
p. 404 - 413
(2020/01/03)
-
- Parecoxib sodium substituted impurity and preparation method thereof
-
The invention relates to a parecoxib sodium substituted impurity and a preparation method thereof. The preparation method comprises the following steps: carrying out a reaction on a compound with a structure represented by a formula I with hydroxylamine h
- -
-
Paragraph 0111-0115
(2020/06/05)
-
- Parecoxib sodium disubstituted impurity as well as preparation method and application thereof
-
The invention relates to a parecoxib sodium disubstituted impurity as well as a preparation method and application thereof. The parecoxib sodium disubstituted impurity has a structure represented by aformula A, the parecoxib sodium impurity can be used as
- -
-
Paragraph 0088; 0092-0095
(2020/06/05)
-
- Degradation versus inhibition: Development of proteolysis-targeting chimeras for overcoming statin-induced compensatory upregulation of 3-hydroxy-3-methylglutaryl coenzyme a reductase
-
3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is an eight-pass transmembrane protein in the endoplasmic reticulum (ER) and a classical drug target to treat dyslipidemia. Statins including the well-known atorvastatin (Lipitor; Pfizer) have been w
- Li, Mei-Xin,Yang, Yiqing,Zhao, Qiuye,Wu, Yue,Song, Lei,Yang, Haiyan,He, Ming,Gao, Hongying,Song, Bao-Liang,Luo, Jie,Rao, Yu
-
p. 4908 - 4928
(2020/06/08)
-
- CEPHALOSPORIN CIPROFLOXACIN HYBRID COMPOUNDS
-
A compound of formula (Ia) and related aspects.
- -
-
Page/Page column 35; 39; 47
(2020/06/05)
-
- Discovery of a potent protein kinase D inhibitor: insights in the binding mode of pyrazolo[3,4-d]pyrimidine analogues
-
In this study, we set out to rationally optimize PKD inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold. The lead compound for this study was 1-NM-PP1, which was previously found by us and others to inhibit PKD. In our screening we identified one compound (3-IN-PP1) displaying a 10-fold increase in potency over 1-NM-PP1, opening new possibilities for specific protein kinase inhibitors for kinases that show sensitivity towards pyrazolo[3,4-d]pyrimidine derived compounds. Interestingly the observed SAR was not in complete agreement with the commonly observed binding mode where the pyrazolo[3,4-d]pyrimidine compounds are bound in a similar fashion as PKD's natural ligand ATP. Therefore we suggest an alternate binding mode where the compounds are flipped 180 degrees. This possible alternate binding mode for pyrazolo[3,4-d]pyrimidine based compounds could pave the way for a new class of specific protein kinase inhibitors for kinases sensitive towards pyrazolo[3,4-d]pyrmidines.
- Verschueren, Klaas,Cobbaut, Mathias,Demaerel, Joachim,Saadah, Lina,Voet, Arnout R. D.,Van Lint, Johan,De Borggraeve, Wim M.
-
p. 640 - 646
(2017/03/30)
-
- Pyrazolo[3,4-c]pyridine derivative
-
The invention relates to a pyrazolo[3,4-c]pyridine derivative. The invention relates to a compound represented by a formula (I), a tautomer thereof, an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein the formula (I) is shown in the description, and Z, X, RNc, RNd, RNe and RNf are defined according to the claim 1. The invention further relates to the pharmaceutical composition contain the compound. The invention further relates to use of the compound or the pharmaceutical composition in preparing a drug for preventing and/or treating a disease which inhibits positive influence of an Xa factor, particularly use in preparing the drug for preventing and/or treating the disease which inhibits positive influence of the Xa factor under the condition of low hemorrhage risk.
- -
-
-
- COMPOUNDS CONTAINING CARBON-CARBON LINKER AS GPR120 AGONISTS
-
The present invention relates to compound of Formula (I) containing carbon-carbon linker, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N -oxide, S-oxide, or a carboxylic aci
- -
-
Page/Page column 55
(2016/09/22)
-
- Rhodium(III)-Catalyzed Cascade Cyclization/Electrophilic Amidation for the Synthesis of 3-Amidoindoles and 3-Amidofurans
-
A rhodium(III)-catalyzed cascade cyclization/electrophilic amidation using N-pivaloyloxylamides as the electrophilic nitrogen source has been developed. This protocol provides an efficient route for the synthesis of 3-amidoindoles and 3-amidofurans under mild conditions with good functional group tolerance. The synthetic utility of this reaction has been demonstrated through the derivatization of the 3-amidoindoles to several heterocycle-fused indoles.
- Hu, Zhiyong,Tong, Xiaofeng,Liu, Guixia
-
supporting information
p. 2058 - 2061
(2016/06/01)
-
- MULTIFUNCTIONAL MONOMERS AND THEIR USE IN MAKING CROSS-LINKED POLYMERS AND POROUS FILMS
-
This invention is a monomer comprising at least two dienophile groups and at least two ring structures which ring structures are characterized by the presence of two conjugated carbon-to-carbon double bonds and the presence of a leaving group L, wherein L is characterized that when the ring structure reacts with a dienophile in the presence of heat or other energy sources, L is removed to form an aromatic ring structure. This invention is also curable oligomers and polymers and highly cross-linked polymers made with such monomers. Moreover, this invention is a method of making porous films by combining such monomers or their oligomers with a porogen, curing the polymer and removing the porogen.
- -
-
Paragraph 0096
(2016/01/25)
-
- Copper-catalyzed base-accelerated direct oxidation of C-H bond to synthesize benzils, isatins, and quinoxalines with molecular oxygen as terminal oxidant
-
We describe herein an efficient and general copper (II)-catalyzed base-accelerated oxidation of the C-H bond to synthesize benzils and isatins. With similar oxidation system an efficient one-pot procedure for the synthesis of quinoxaline derivatives was realized. The two protocols feature using molecular oxygen as terminal oxidant, low catalyst loading, wide substrate scope, and high functional-group tolerance.
- Yu, Jing-Wen,Mao, Shuai,Wang, Yong-Qiang
-
p. 1575 - 1580
(2015/03/14)
-
- HETEROCYCLIC GROUP CONTAINED AMINO-METHANOL DERIVATIVE, AND SALT, SYNTHETIC METHOD AND USE THEREOF
-
The present invention provides a heterocyclic group contained amino-methanol derivative, and salt, a preparation method and use thereof, and belongs to the medical field. The heterocyclic group contained amino-methanol derivative and the salt thereof of the present invention are used for preparing medicines for immune suppression and for the treatment of organ transplant rejection, or medicines for treating immune mediated inflammatory diseases, such as multiple sclerosis, systemic lupus erythematosus and rheumatoid arthritis.
- -
-
Paragraph 0133 - 0135
(2015/04/15)
-
- HETEROCYCLIC GROUP CONTAINED AMINO-METHANOL DERIVATIVE, AND SALT, SYNTHETIC METHOD AND USE THEREOF
-
The present invention provides a heterocyclic group contained amino-methanol derivative, and salt, a preparation method and use thereof, and belongs to the medical field. The heterocyclic group contained amino-methanol derivative and the salt thereof of the present invention are used for preparing medicines for immune suppression and for the treatment of organ transplant rejection , or medicines for treating immune mediated inflammatory diseases, such as multiple sclerosis, systemic lupus erythematosus and rheumatoid arthritis.
- -
-
Paragraph 0081; 0082; 0083
(2015/04/22)
-
- Design and synthesis of thiazole derivatives as potent FabH inhibitors with antibacterial activity
-
Components of fatty acid biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. Compounds of series A (4a-4g) and series B (5a-5g) were synthesized by the formation of an amine bond between aromati
- Li, Jing-Ran,Li, Dong-Dong,Wang, Rong-Rong,Sun, Jian,Dong, Jing-Jun,Du, Qian-Ru,Fang, Fei,Zhang, Wei-Ming,Zhu, Hai-Liang
-
p. 438 - 447
(2014/03/21)
-
- Optimizing small molecule inhibitors of calcium-dependent protein kinase 1 to prevent infection by toxoplasma gondii
-
Toxoplasma gondii is sensitive to bulky pyrazolo [3,4-d] pyrimidine (PP) inhibitors due to the presence of a Gly gatekeeper in the essential calcium dependent protein kinase 1 (CDPK1). Here we synthesized a number of new derivatives of 3-methyl-benzyl-PP (3-MB-PP, or 1). The potency of PP analogues in inhibiting CDPK1 enzyme activity in vitro (low nM IC50 values) and blocking parasite growth in host cell monolayers in vivo (low μM EC 50 values) were highly correlated and occurred in a CDPK1-specific manner. Chemical modification of the PP scaffold to increase half-life in the presence of microsomes in vitro led to identification of compounds with enhanced stability while retaining activity. Several of these more potent compounds were able to prevent lethal infection with T. gondii in the mouse model. Collectively, the strategies outlined here provide a route for development of more effective compounds for treatment of toxoplasmosis and perhaps related parasitic diseases.
- Lourido, Sebastian,Zhang, Chao,Lopez, Michael S.,Tang, Keliang,Barks, Jennifer,Wang, Qiuling,Wildman, Scott A.,Shokat, Kevan M.,Sibley, L. David
-
p. 3068 - 3077
(2013/06/05)
-
- BACE1 inhibitors: A head group scan on a series of amides
-
A series of amides bearing a variety of amidine head groups was investigated as BACE1 inhibitors with respect to inhibitory activity in a BACE1 enzyme as well as a cell-based assay. Determination of their basicity as well as their properties as substrates
- Woltering, Thomas J.,Wostl, Wolfgang,Hilpert, Hans,Rogers-Evans, Mark,Pinard, Emmanuel,Mayweg, Alexander,G?bel, Martin,Banner, David W.,Benz, J?rg,Travagli, Massimiliano,Pollastrini, Martina,Marconi, Guido,Gabellieri, Emanuele,Guba, Wolfgang,Mauser, Harald,Andreini, Matteo,Jacobsen, Helmut,Power, Eoin,Narquizian, Robert
-
supporting information
p. 4239 - 4243
(2013/07/26)
-
- Vaulted biaryls in catalysis: A structure-activity relationship guided tour of the immanent domain of the VANOL ligand
-
The active site in the BOROX catalyst is a chiral polyborate anion (boroxinate) that is assembled in situ from three equivalents of B(OPh) 3 and one of the VANOL ligand by a molecule of substrate. The substrates are bound to the boroxinate by Hbonds to oxygen atoms O1-O3. The effects of introducing substituents at each position of the naphthalene core of the VANOL ligand are systematically investigated in an aziridination reaction. Substituents in the 4,4′- and 8,8′-positions have a negative effect on catalyst performance, whereas, substituents in the 7- and 7′-positions have the biggest impact in a positive direction. VANOL destination: The active site in the BOROX catalyst is a chiral polyborate anion (boroxinate; see figure) that is assembled in situ from three equivalents of B(OPh)3 and one of the VANOL ligand by a molecule of substrate. The effects of introducing substituents at each position of the naphthalene core of the VANOL ligand are systematically investigated in an aziridination reaction. Copyright
- Guan, Yong,Ding, Zhensheng,Wulff, William D.
-
supporting information
p. 15565 - 15571
(2013/11/19)
-
- Discovery of 4,6-substituted-(diaphenylamino)quinazolines as potent c-Src inhibitors
-
A series of 4,6-substituted-(diaphenylamino)quinazolines as c-Src inhibitors have been prepared and their biological activity has also been evaluated. All the compounds displayed potential antiproliferation activities, with IC50 values ranging from 3.42 μM to 118.81 μM in five human tumor cell lines. Particularly, compound 15 exhibited higher cytotoxicity against the tested five tumor cell lines compared to the other small molecules. Generally, most of these compounds showed selectivity between the A549 cells and the other four cells, according to their corresponding IC50 values. The results obtained from the in vitro enzyme assay indicated compound 15 has remarkable inhibitory activity against c-Src kinase with an IC50 value of 27.3 nM, which is comparable to the control compounds. Furthermore, molecular docking and QSAR study by means of DS 3.5 (Discovery Studio 3.5, Accelrys, Co. Ltd) explored the binding modes and the structure and activity relationship (SAR) of these derivatives.
- Li, Jing-Ran,Li, Dong-Dong,Fang, Fei,Du, Qian-Ru,Lin, Lin,Sun, Jian,Qian, Yong,Zhu, Hai-Liang
-
p. 8375 - 8386
(2013/12/04)
-
- Design, synthesis, and biological activity of potent and orally available g protein-coupled receptor 40 agonists
-
G protein-coupled receptor 40 (GPR40) is being recently considered to be a new potential drug target for the treatment of type 2 diabetes because of its role in the enhancement of free fatty acid-regulated glucose-stimulated insulin secretion in pancreatic β-cells. We initially identified benzyloxyphenylpropanoic acid (1b) (EC50 = 510 nM), which was designed based on the structure of free fatty acids, as a promising lead compound with GPR40 agonist activity. Chemical modification of compound 1b led to the discovery of 3-{4-[(2′,6′-dimethylbiphenyl-3-yl)methoxy]-2- fluorophenyl}propanoic acid (4p) as a potent GPR40 agonist (EC50 = 5.7 nM). Compound 4p exhibited acceptable pharmacokinetic profiles and significant glucose-lowering effects during an oral glucose tolerance test in diabetic rats. Moreover, no hypoglycemic event was observed even after administration of a high dose of compound 4p to normal fasted rats. These pharmacological results suggest that GPR40 agonists might be novel glucose-dependent insulin secretagogues with little or no risk of hypoglycemia.
- Sasaki, Shinobu,Kitamura, Shuji,Negoro, Nobuyuki,Suzuki, Masami,Tsujihata, Yoshiyuki,Suzuki, Nobuhiro,Santou, Takashi,Kanzaki, Naoyuki,Harada, Masataka,Tanaka, Yasuhiro,Kobayashi, Makoto,Tada, Norio,Funami, Miyuki,Tanaka, Toshimasa,Yamamoto, Yoshio,Fukatsu, Kohji,Yasuma, Tsuneo,Momose, Yu
-
experimental part
p. 1365 - 1378
(2011/05/05)
-
- Synthesis, biological evaluation and molecular docking studies of 1,3,4-thiadiazole derivatives containing 1,4-benzodioxan as potential antitumor agents
-
A series of 1,3,4-thiadiazole derivatives containing 1,4-benzodioxan (2a-2s) have been synthesized to screen for FAK inhibitory activity. Compound 2p showed the most potent biological activity against HEPG2 cancer cell line (EC50 = 10.28 μg/mL
- Sun, Juan,Yang, Yu-Shun,Li, Wei,Zhang, Yan-Bin,Wang, Xiao-Liang,Tang, Jian-Feng,Zhu, Hai-Liang
-
scheme or table
p. 6116 - 6121
(2011/10/31)
-
- 2,5,6,7-TETRAHYDRO-[1,4]OXAZEPIN-3-YLAMINE OR 2,3,6,7-TETRAHYDRO-[1,4]OXAZEPIN-5-YLAMINE COMPOUNDS
-
This invention relates to compounds of the formula (I), wherein A, B and R1 to R7 are as described below, or to pharmaceutically acceptable salts thereof. These compounds are BACE1 and/or BACE2 inhibitors and can be used as 5 medicam
- -
-
Page/Page column 110
(2011/11/30)
-
- 2,5,6,7-TETRAHYDRO-[1,4]OXAZEPIN-3-YLAMINE OR 2,3,6,7-TETRAHYDRO-[1,4]OXAZEPIN-5-YLAMINE COMPOUNDS
-
This invention relates to compounds of the formula wherein A, B and R1 to R7 are as described below, or to pharmaceutically acceptable salts thereof. These compounds are BACE1 and/or BACE2 inhibitors and can be used as medicaments fo
- -
-
Page/Page column 50
(2012/01/13)
-
- GLUCAGON ANTAGONISTS
-
Provided herein are compounds, including enantiomerically pure forms thereof, and pharmaceutically acceptable salts or co-crystals and prodrugs thereof which have glucagon receptor antagonist or inverse agonist activity. Further, provided herein are pharm
- -
-
Page/Page column 49
(2010/04/03)
-
- Identification of novel urease inhibitors by high-throughput virtual and in vitro screening
-
Ureases are important in both agriculture and human health. Bacterial ureases are directly involved in many farm-field problems and pathological conditions. Here, we report a structure-based virtual screening of an in-house compound bank of about 6000 molecular entities by computational docking and binding free energy calculations followed by in vitro screening. Applied protocol leads to the identification of novel urease inhibitors, which can serve as starting points for structural optimization.
- Abid, Obaid-Ur-Rahman,Babar, Tariq Mahmood,Ali, Farukh Iftakhar,Ahmed, Shahzad,Wadood, Abdul,Rama, Nasim Hasan,Uddin, Reaz,Zaheer-Ul-Haq,Khan, Ajmal,Choudhary, M. Iqbal
-
scheme or table
p. 145 - 149
(2010/10/19)
-
- Practical and chemoselective reduction of acyl chloride to alcohol by borohydride in aqueous dichloromethane
-
A simple methodology for the reduction of acid chlorides to their corresponding alcohols has been developed. Various carboxylic acids were converted to alcohols in excellent yields using NaBH4-K2CO3 in a mixed solvent system of dichloromethane and water (1:1) in the presence of a phase-transfer catalyst at low temperature. The importance of the work is its simplicity, selectivity, excellent yield, and very short reaction time. This new reduction condition has proved to be an excellent chemoselective method for a range of acid chlorides in the presence of various functional groups.
- Rajan, Ramya,Badgujar, Sachin,Kaur, Kamaljit,Malpani, Yashwardhan,Kanjilal, Pranab R.
-
experimental part
p. 2897 - 2907
(2010/11/18)
-
- PHTHALAZINONE DERIVATIVES
-
A compound of the formula (I): wherein: A and B together represent an optionally substituted, fused aromatic ring; X and Y are selected from CH and CH, CF and CH, CH and CF and N and CH respectively; RC is selected from H, C1-4 alkyl
- -
-
Page/Page column 39
(2009/08/14)
-
- An investigation into the electrophilic cyclisation of N-acyl-pyrrolidinium ions: A facile synthesis of Pyrrolo-tetrahydroisoquinolones and Pyrrolo-benzazepinones
-
The triflic acid-mediated cyclisation of N-arylmethyl- and N-arylethyl-acylpyrrolidinium ions gave moderate to good yields of pyrrolo-tetrahydroisoquinolones and pyrrolo-benzazepinones respectively. Electron-donating R substituents enhanced the rate of reaction and gave higher yields than electron-withdrawing substituents. Substituents on the methyl or ethyl chain in general enhanced the reaction, unless sterically encumbered. The equivalent acylpiperidinium ions cyclised much slower and in lower yield.
- King, Frank D.,Aliev, Abil E.,Caddick, Stephen,Copley, Royston C. B.
-
experimental part
p. 3561 - 3571
(2010/01/06)
-
- PYRROLO ISOQUINOLINES AS KINASE INHIBITORS
-
A compound of formula (I) or a pharmaceutically acceptable salt or prodrug ester thereof: wherein the groups R1, R2, R3, R7 and X are as defined in the specification.
- -
-
Page/Page column 70
(2008/06/13)
-
- BICYCLIC SPIROHYDANTOIN CGRP RECEPTOR ANTAGONISTS
-
Compounds of formula I: (wherein variables A1, A2, A3, A4, A5, A6, A7, B, E1, E2, E3, E4, E5, G1, G2
- -
-
Page/Page column 58; 79-80
(2008/06/13)
-
- SPIROHYDANTOIN ARYL CGRP RECEPTOR ANTAGONISTS
-
Compounds of formula (I); (wherein variables A1, A2. A3, A4, A5, A6, A7, B3 E1, E2, E3, E4, E5, G1, G2 and R.6 are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
- -
-
Page/Page column 60-61
(2008/06/13)
-
- SPIROHYDANTOIN TRICYCLIC CGRP RECEPTOR ANTAGONISTS
-
Compounds of formula I: (wherein variables A1, A2, A3, A4, A5, A6, A7, B1, B2, B3, B4, D1, D2, E1, E2, E3, E4, E5, G1, G2, R6, T, U, V, W, X, Y and Z are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
- -
-
Page/Page column 51; 71-72
(2008/06/13)
-
- FUSED HETEROCYCLIC COMPOUND AND USE THEREOF
-
The present invention relates to wherein each symbol is as defined in the specification. The compound has a superior mineral corticoidreceptorantagonistic action and is useful as an agent for the prophylaxis or treatment of hypertension, cardiac failure and the like, a compound having a fused heterocycle, or a prodrug thereof, or a salt thereof; and an agent for the prophylaxis or treatment of hypertension, cardiac failure and the like.
- -
-
Page/Page column 347
(2008/06/13)
-
- TRICYCLIC ANILIDE SPIROHYDANTOIN CGRP RECEPTOR ANTAGONISTS
-
The present invention is directed to compounds of Formula I: I (where A1, A2, B1, B2, B3, B4, D1, D2, T, U, V, W, X, Y, Z, R4, R5a?, R5b/su
- -
-
Page/Page column 31; 45
(2008/06/13)
-
- Compositions and methods of treating cell proliferation disorders
-
The invention relates to compounds and methods for treating cell proliferation disorders.
- -
-
Page/Page column 73-74
(2008/06/13)
-
- The diazo route to diazonamide A. Studies on the indole bis-oxazole fragment
-
Various approaches to the indole bis-oxazole fragment of the marine secondary metabolite diazonamide A are described, all of which feature dirhodium(II)-catalyzed reactions of diazocarbonyl compounds in key steps. Thus, 3-bromophenylacetaldehyde is conver
- Davies, James R.,Kane, Peter D.,Moody, Christopher J.
-
p. 7305 - 7316
(2007/10/03)
-
- Bisphosphonate inhibition of the exopolyphosphatase activity of the Trypanosoma brucei soluble vacuolar pyrophosphatase
-
Trypanosoma brucei, the causative agent of African trypanosomiasis, contains a soluble, vacuolar pyrophosphatase, TbVSP1, not present in humans, which is essential for the growth of bloodstream forms in their mammalian host. Here, we report the inhibition of a recombinant TbVSP1 expressed in Escherichia coli by a panel of 81 bisphosphonates. The IC50 values were found to vary from ~2 to 850 μM. We then used 3D QSAR (comparative molecular field and comparative molecular similarity index; CoMFA and CoMSIA) methods to analyze the enzyme inhibition results. The R2 values for the experimental versus the QSAR-predicted activities were 0.78 or 0.61 for CoMFA and 0.79 or 0.68 for CoMSIA, for two different alignments. The root-mean-square (rms) pIC50 error for the best CoMFA model was 0.41 for five test sets of five activity predictions, which translates to a factor of ~2.6 error in IC50 prediction. For CoMSIA, the rms pIC50 error and error factors were 0.35 and 2.2, respectively. In general, the most active compounds contained both a single aromatic ring and a hydrogen bond donor feature. Thirteen of the more potent compounds were then tested in vivo in a mouse model of T. brucei infection. The most active compound in vivo provided a 40% protection from death with no apparent side effects, suggesting that further development of such compounds may be of interest.
- Kotsikorou, Evangelia,Song, Yongcheng,Chan, Julian M. W.,Faelens, Stephanie,Tovian, Zev,Broderick, Erin,Bakalara, Norbert,Docampo, Roberta,Oldfield, Eric
-
p. 6128 - 6139
(2007/10/03)
-
- Substituted tetrahydroisoquinoline compounds, methods of making, and their use
-
The present invention relates to novel substituted tetrahydroisoquinoline compounds, pharmaceutical compositions containing the compounds, methods of making the compounds, and methods of using the compounds to destroy a target cell, such as a cancer cell,
- -
-
Page/Page column 20
(2010/02/05)
-
- Structure-activity relationship of linear peptide Bu-His-DPhe-Arg-Trp-Gly-NH2 at the human melanocortin-1 and -4 receptors: Histidine substitution
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Systematic substitution of His6 residue using non-selective hMC4R pentapeptide agonist (Bu-His6-DPhe7-Arg8-Trp9-Gly 10-NH2) as the template led to the identification of Bu-Atcsu
- Cheung, Adrian Wai-Hing,Danho, Waleed,Swistok, Joseph,Qi, Lida,Kurylko, Grazyna,Rowan, Karen,Yeon, Mitch,Franco, Lucia,Chu, Xin-Jie,Chen, Li,Yagaloff, Keith
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p. 133 - 137
(2007/10/03)
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- Antiplatelet activity of synthetic pyrrolo-benzylisoquinolines
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Pyrrolo-benzylisoquinolines were prepared as target compounds and their antiplatelet aggregation activity, adreno-receptor affinity, and cytotoxicity were screened. Compounds 1d-9d showed specific antiplatelet aggregation activity induced by arachidonic acid and collagen. Among them, 8d and 9d exhibited better activity than the reference drug, aspirin and 9d also showed inhibition of platelet aggregation by all four inducers.
- Kuo, Reen-Yen,Wu, Chin-Chung,Chang, Fang-Rong,Yeh, Jwu-Lai,Chen, Ing-Jun,Wu, Yang-Chang
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p. 821 - 823
(2007/10/03)
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- Structure-based design of carboxybiphenylindole inhibitors of the ZipA-FtsZ interaction.
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Structural features of two weak inhibitors of the ZipA-FtsZ protein-protein interaction which were found to bind to overlapping but different areas of the key binding site were combined in one new series of carboxybiphenyl-indoles with improved inhibitory
- Sutherland, Alan G,Alvarez, Juan,Ding, Weidong,Foreman,Kenny, Cynthia Hess,Labthavikul, Pornpen,Mosyak, Lidia,Petersen, Peter J,Rush 3rd., Thomas S,Ruzin, Alexey,Tsao, Desiree H H,Wheless, Karen L
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p. 4138 - 4140
(2007/10/03)
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- 3-(Arylacetylamino)-N-methylbenzamides: A novel class of selective anti-Helicobacter pylori agents
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After chemical modification preceded by the random screening of our chemical library, a novel class of selective anti-Helicobacter pylori agents was generated. Consequently, the 3-(arylacetylamino)-N-methylbenzamides, which were quite easy to prepare, showed potent inhibitory activity against Helicobacter pylori but exhibited no inhibitory activity against other sorts of bacteria and fungi, e.g., Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Bacteroides fragilis, and Candida albicans. These compounds showed potent anti-H. pylori activity under acidic conditions, whereas amoxicillin and clarithromycin decreased activity. The 3-(3-arylpropionylamino)-N-methylbenzamides, 3-(aryloxyacetylamino)-N-methylbenzamides, and (3-methylcarbamoylphenyl)carbamic acid 1-arylmethyl esters also exhibited potent anti-H. pylori activity. Finally, we selected 7n (BAS-118) as a candidate compound for further evaluation.
- Ando,Kawamura,Chiba
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p. 4468 - 4474
(2007/10/03)
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- Quinolones as gonadotropin releasing hormone (GnRH) antagonists: Simultaneous optimization of the C(3)-aryl and C(6)-substituents
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A series of 3-arylquinolones was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists. A variety of substitution patterns of the 3-aryl substituent are described. The 3,4,5-trimethylphenyl substituent (23h) was found to be optimal. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Young, Jonathan R.,Huang, Song X.,Chen, Irene,Walsh, Thomas F.,DeVita, Robert J.,Wyvratt Jr., Matthew J.,Goulet, Mark T.,Ren, Ning,Lo, Jane,Yang, Yi Tien,Yudkovitz, Joel B.,Cheng, Kang,Smith, Roy G.
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p. 1723 - 1727
(2007/10/03)
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- Non-acidic antiinfiammatory compounds II. Synthesis and activity of 6-amino-2,4-lutidine derivatives
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Benzamides I, phenylalkanamides II and cinnamamides III are structurally related to the antiinflammatory N-(4,6-dimethylpyridin-2-yl)benzamide I. These were synthesized and the transformation of the 2-aminopyridine nucleus of benzamides I into a 2-imino-1,2-dihydropyridine structure (compounds IV) was also carried out. Of the 49 new derivatives, the 3-fluorobenzamide 9 was the most patent in the oral treatment of carrageenen-induced peripheral edema; IC50 = 12.2 mg·kg-1. It was 3 times as active as benzamide 1, but the latter nevertheless had a better therapeutic index (LD5(/)IC50) of 52 against 23. Benzamide 1, a non-acidic antiinflammatory compound devoid of any blocking activity on cyclooxygenase, markedly reduces the production of reactive oxygen species in rat peritoneal macrophages. This compound probably acts at the membrane, perhaps by interference with transmembrane events.
- Robert,Robert-Piessard,Duflos,Le Baut,Khettab,Grimaud,Petit,Welin
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p. 841 - 854
(2007/10/02)
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