共查询到20条相似文献,搜索用时 15 毫秒
1.
Li J Lynch MP Demello KL Sakya SM Cheng H Rafka RJ Bronk BS Jaynes BH Kilroy C Mann DW Haven ML Kolosko NL Petras C Seibel SB Lund LA 《Bioorganic & medicinal chemistry》2005,13(5):1805-1809
The synthesis of a novel canine COX-2 selective inhibitor, 2-(3-difluoromethyl-5-phenylpyrazol-1-yl)-5-methanesulfonylpyridine, and its in vitro and in vivo profile are described. Pyrazole 8 demonstrated excellent potency and selectivity for canine COX-2 in both in vitro and ex vivo whole blood assays. This novel COX-2 inhibitor also showed a good pharmacokinetic profile (pk) following oral (po), intravenous (iv), and subcutaneous (sc) dosing and demonstrated excellent in vivo efficacy in a canine synovitis model. 相似文献
2.
Junliang Hao Veronique Dehlinger Adam M. Fivush Helene C.E. Rudyk Thomas C. Britton Sean P. Hollinshead Benjamin P. Vokits Barry P. Clark Steven S. Henry Steven M. Massey Langu Peng Bruce A. Dressman Beverly A. Heinz Edda F. Roberts Mallorie R. Bracey-Walker Steven Swanson John T. Catlow Patrick L. Love James A. Monn 《Bioorganic & medicinal chemistry letters》2013,23(5):1249-1252
A novel series of selective negative allosteric modulators (NAMs) for metabotropic glutamate receptor 5 (mGlu5) was discovered from an isothiazole scaffold. One compound of this series, (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide (24), demonstrated satisfactory pharmacokinetic properties and, following oral dosing in rats, produced dose-dependent and long-lasting mGlu5 receptor occupancy. Consistent with the hypothesis that blockade of mGlu5 receptors will produce analgesic effects in mammals, compound 24 produced a dose-dependent reduction in paw licking responses in the formalin model of persistent pain. 相似文献
3.
Mark J. Ammirati Kim M. Andrews David D. Boyer Anne M. Brodeur Dennis E. Danley Shawn D. Doran Bernard Hulin Shenping Liu R. Kirk McPherson Stephen J. Orena Janice C. Parker Jana Polivkova Xiayang Qiu Carolyn B. Soglia Judith L. Treadway Maria A. VanVolkenburg Donald C. Wilder David W. Piotrowski 《Bioorganic & medicinal chemistry letters》2009,19(7):1991-1995
A series of 4-substituted proline amides was synthesized and evaluated as inhibitors of dipeptidyl pepdidase IV for the treatment of type 2 diabetes. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone (5) emerged as a potent (IC50 = 13 nM) and selective compound, with high oral bioavailability in preclinical species and low plasma protein binding. Compound 5, PF-00734200, was selected for development as a potential new treatment for type 2 diabetes. 相似文献
4.
Penglie Zhang Wenrong Huang Lingyan Wang Liang Bao Zhaozhong J. Jia Shawn M. Bauer Erick A. Goldman Gary D. Probst Yonghong Song Ting Su Jingmei Fan Yanhong Wu Wenhao Li John Woolfrey Uma Sinha Paul W. Wong Susan T. Edwards Ann E. Arfsten Lane A. Clizbe James Kanter Bing-Yan Zhu 《Bioorganic & medicinal chemistry letters》2009,19(8):2179-2185
Systematic SAR studies of in vitro factor Xa inhibitory activity around compound 1 were performed by modifying each of the three phenyl rings. A class of highly potent, selective, efficacious and orally bioavailable direct factor Xa inhibitors was discovered. These compounds were screened in hERG binding assays to examine the effects of substitution groups on the hERG channel affinity. From the leading compounds, betrixaban (compound 11, PRT054021) has been selected as the clinical candidate for development. 相似文献
5.
Jinhwa Lee Hee Jeong Seo Suk Ho Lee Jeongmin Kim Myung Eun Jung Sung-Han Lee Kwang-Seop Song Junwon Lee Suk Youn Kang Min Ju Kim Mi-Soon Kim Eun-Jung Son MinWoo Lee Ho-Kyun Han 《Bioorganic & medicinal chemistry》2010,18(17):6377-6388
Structure–activity relationship studies in a series of diarylpyrazolyl thiadiazoles identified cannabinoid-1 receptor antagonists with excellent potency and selectivity. Based on its exceptional in vivo efficacy in animal models and its favorable pharmacokinetic and toxicological profiles, 2-(4-((1H-1,2,4-triazol-1-yl)methyl)-5-(4-bromophenyl)-1-(2-chlorophenyl)-1H-pyrazol-3-yl)-5-tert-butyl-1,3,4-thiadiazole (GCC2680) was selected as a preclinical candidate for the treatment of obesity. 相似文献
6.
Zhang P Terefenko E Kern J Fensome A Trybulski E Unwalla R Wrobel J Lockhead S Zhu Y Cohen J Lacava M Winneker RC Zhang Z 《Bioorganic & medicinal chemistry》2007,15(20):6556-6564
We have recently discovered 5-(3-cyclopentyl-2-thioxo-2,3-dihydro-1H-benzimidazol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (14) as a potent, selective, and orally active non-steroidal progesterone receptor (PR) agonist. Compound 14 and its analog 13 possessed sub-nanomolar in vitro potency (EC(50) 0.1-0.5nM) in the T47D alkaline phosphatase assay, similar to that of the steroidal PR agonist medroxyprogesterone acetate (MPA). In contrast to MPA, 14 was highly selective (>500-fold) for the PR over both glucocorticoid and androgen receptors. In the rat uterine decidualization and complement component C3 models, 14 had oral ED(50) values of 0.02 and 0.003mg/kg, respectively, and was from 6- to 20-fold more potent than MPA. In the monkey ovulation inhibition model, compound 14 was also highly efficacious and potent with an oral ED(100) of 0.03mg/kg. 相似文献
7.
Ranatunge RR Earl RA Garvey DS Janero DR Letts LG Martino AM Murty MG Richardson SK Schwalb DJ Young DV Zemtseva IS 《Bioorganic & medicinal chemistry letters》2004,14(24):429-6052
A series of 3-(2-methoxytetrahydrofuran-2-yl)pyrazoles (4–10) was synthesized. The compounds were evaluated for their ability to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) activity in human whole blood (HWB). The compound, 5-(4-methanesulfonylphenyl)-3-(2-methoxytetrahydrofuran-2-yl)-1-p-tolyl-1H-pyrazole 5 showed potent and selective COX-2 inhibition (IC50 for COX-1: >100 μM and COX-2: 1.2 μM). 相似文献
8.
Ishida H Isami S Matsumura T Umehara H Yamashita Y Kajita J Fuse E Kiyoi H Naoe T Akinaga S Shiotsu Y Arai H 《Bioorganic & medicinal chemistry letters》2008,18(20):5472-5477
5-(1,3,4-Oxadiazol-2-yl)pyrimidine derivative 1 was identified as a new class of FLT3 inhibitor from our compound library. With the aim of enhancement of antitumor activity of 2 prepared by minor modification of 1, structure optimization of side chains at the 2-, 4-, and 5-positions of the pyrimidine ring of 2 was performed to improve the metabolic stability. Introduction of polar substituents on the 1,3,4-oxadiazolyl group contributed to a significant increase in the metabolic stability. As a result, a series of compounds showed increased efficacy against MOLM-13 xenograft model in mice by oral administration. 相似文献
9.
Fujimoto T Kunitomo J Tomata Y Nishiyama K Nakashima M Hirozane M Yoshikubo S Hirai K Marui S 《Bioorganic & medicinal chemistry letters》2011,21(21):6414-6416
During our efforts to identify a series of potent, selective, orally active human Orexin-2 Receptor (OX2R) antagonists, we elucidated structure-activity relationship (SAR) on the 7-position of a benzoxazepine scaffold by utilizing Hammett σ(p) and Hansch-Fujita π value as aromatic substituent constants. The attempts led to the discovery of compound 1m, possessing good in vitro potency with over 100-fold selectivity against OX1R, good metabolic stability in human and rat liver microsome, good oral bioavailability in rats, and in vivo antagonistic activity in rats by oral administration. 相似文献
10.
Huang D Poon SF Chapman DF Chung J Cramer M Reger TS Roppe JR Tehrani L Cosford ND Smith ND 《Bioorganic & medicinal chemistry letters》2004,14(22):5473-5476
Structure-activity relationship studies on 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile 2 led to the discovery of 2-(2-[3-(pyridin-3-yloxy)phenyl]-2H-tetrazol-5-yl)pyridine (10)-a highly potent and selective mGlu5 receptor antagonist with good brain penetration and in vivo receptor occupancy in rat and cross-species oral bioavailability. 相似文献
11.
Discovery of L-791,943: a potent,selective, non emetic and orally active phosphodiesterase-4 inhibitor 总被引:3,自引:0,他引:3
Guay D Hamel P Blouin M Brideau C Chan CC Chauret N Ducharme Y Huang Z Girard M Jones TR Laliberté F Masson P McAuliffe M Piechuta H Silva J Young RN Girard Y 《Bioorganic & medicinal chemistry letters》2002,12(11):1457-1461
Structure-activity relationship studies directed toward improving the potency and metabolic stability of CDP-840 (3) resulted in the discovery of L-791,943 (11n) as a potent (HWB TNF-alpha = 0.67 microM) and orally active phosphodiesterase type 4 (PDE4) inhibitor. This compound, which bears a stable bis-difluoromethoxy catechol and a pendant hexafluorocarbinol, exhibited a long half-life in rat and in squirrel monkey. It is well tolerated in ferret with an emetic threshold greater than 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig and in the ascaris-induced bronchoconstriction models in sheep and squirrel monkey. 相似文献
12.
Tomohiro Yoshida Fumihiko Akahoshi Hiroshi Sakashita Hiroshi Kitajima Mitsuharu Nakamura Shuji Sonda Masahiro Takeuchi Yoshihito Tanaka Naoko Ueda Sumie Sekiguchi Takayuki Ishige Kyoko Shima Mika Nabeno Yuji Abe Jun Anabuki Aki Soejima Kumiko Yoshida Yoko Takashina Shinichi Ishii Satoko Kiuchi Yoshiharu Hayashi 《Bioorganic & medicinal chemistry》2012,20(19):5705-5719
Dipeptidyl peptidase IV (DPP-4) inhibition is suitable mechanism for once daily oral dosing regimen because of its low risk of hypoglycemia. We explored linked bicyclic heteroarylpiperazines substituted at the γ-position of the proline structure in the course of the investigation of l-prolylthiazolidines. The efforts led to the discovery of a highly potent, selective, long-lasting and orally active DPP-4 inhibitor, 3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine (8g), which has a unique structure characterized by five consecutive rings. An X-ray co-crystal structure of 8g in DPP-4 demonstrated that the key interaction between the phenyl ring on the pyrazole and the S2 extensive subsite of DPP-4 not only boosted potency, but also increased selectivity. Compound 8g, at 0.03 mg/kg or higher doses, significantly inhibited the increase of plasma glucose levels after an oral glucose load in Zucker fatty rats. Compound 8g (teneligliptin) has been approved for the treatment of type 2 diabetes in Japan. 相似文献
13.
Bamborough P Christopher JA Cutler GJ Dickson MC Mellor GW Morey JV Patel CB Shewchuk LM 《Bioorganic & medicinal chemistry letters》2006,16(24):6236-6240
The identification and hit-to-lead exploration of a novel, potent and selective series of substituted benzimidazole–thiophene carbonitrile inhibitors of IKK-ε kinase is described. Compound 12e was identified with an IKK-ε enzyme potency of pIC50 7.4, and has a highly encouraging wider selectivity profile, including selectivity within the IKK kinase family. 相似文献
14.
Altenburger JM Lassalle GY Matrougui M Galtier D Jetha JC Bocskei Z Berry CN Lunven C Lorrain J Herault JP Schaeffer P O'Connor SE Herbert JM 《Bioorganic & medicinal chemistry》2004,12(7):1713-1730
SSR182289A 1 is the result of a rational optimisation process leading to an orally active thrombin inhibitor. The structure incorporates an original 2-(acetylamino)-[1,1'-biphenyl]-3-sulfonyl N-terminal motif, a central l-Arg surrogate carrying a weakly basic 3-amino-pyridine, and an unusual 4-difluoropiperidine at the C-terminus. Its synthesis is convergent and palladium catalysis has been employed for the construction of the key C-C bonds: Suzuki coupling for the bis-aryl fragment and Sonogashira reaction for the delta- bond of the central amino-acid chain. The compound is a potent inhibitor of thrombin's activities in vitro and demonstrates potent oral anti-thrombotic potencies in three rat models of thrombosis. The observed in vitro potency could be rationalized through the examination of the interactions within the SSR182289A 1 - thrombin crystal structure. SSR182289A 1, has been therefore selected for further development. 相似文献
15.
C Brideau C Chan S Charleson D Denis J F Evans A W Ford-Hutchinson R Fortin J W Gillard J Guay D Guévremont 《Canadian journal of physiology and pharmacology》1992,70(6):799-807
MK-0591 (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-yl-methoxy)- indol-2-yl]-2,2-dimethyl propanoic acid, previously L-686,708) is a potent inhibitor of leukotriene (LT) biosynthesis in intact human and elicited rat polymorphonuclear leukocytes (PMNLs) (IC50 values 3.1 and 6.1 nM, respectively) and in human, squirrel monkey, and rat whole blood (IC50 values 510, 69, and 9 nM, respectively). MK-0591 had no effect on rat 5-lipoxygenase. MK-0591 has a high affinity for 5-lipoxygenase activating protein (FLAP) as evidenced by an IC50 value of 1.6 nM in a FLAP binding assay and inhibition of the photoaffinity labelling of FLAP by two different photoaffinity ligands. Inhibition of activation of 5-lipoxygenase was shown through inhibition of the translocation of the enzyme from the cytosol to the membrane in human PMNLs. MK-0591 was a potent inhibitor of LT biosynthesis in vivo, first, following ex vivo challenge of blood obtained from treated rats and squirrel monkeys, second, in a rat pleurisy model, and, third, as monitored by inhibition of the urinary excretion of LTE4 in antigen-challenged allergic sheep. Inhibition of antigen-induced bronchoconstriction by MK-0591 was observed in inbred rats pretreated with methysergide, Ascaris-challenged squirrel monkeys, and Ascaris-challenged sheep (early and late phase response). These results indicate that MK-0591 is a potent inhibitor of LT biosynthesis both in vitro and in vivo indicating that the compound will be suitable for assessing the role of leukotrienes in pathological situations. 相似文献
16.
Sakya SM DeMello KM Minich ML Rast B Shavnya A Rafka RJ Koss DA Cheng H Li J Jaynes BH Ziegler CB Mann DW Petras CF Seibel SB Silvia AM George DM Lund LA St Denis S Hickman A Haven ML Lynch MP 《Bioorganic & medicinal chemistry letters》2006,16(2):288-292
Structure-activity relationship (SAR) studies of the novel 2-[3-di and trifluoromethyl-5-alkylamino pyrazo-1-yl]-5-methanesulfonyl (SO(2)Me)/sulfamoyl (SO(2)NH(2))-pyridine derivatives for canine COX enzymes are described. The studies led to the identification of 2e as lead with potent in vitro activity, selectivity, and in vivo activity in dogs and cats. 相似文献
17.
Hojin Choi Jaekwang Lee Young Hoon Kim Dai Sig Im In-Chang Hwang Soo Jin Kim Seung Kee Moon Hong Woo Lee Sung Sook Lee Soon Kil Ahn Sang Woong Kim Nam Song Choi Kyung Joo Lee 《Bioorganic & medicinal chemistry letters》2010,20(1):383-386
In a continuing effort to discover novel PDE5 inhibitors, we have successfully found quinazolines with 4-benzylamino substitution as potent and selective PDE5 inhibitors. Initial lead compound (1) was found to be easily metabolized when incubated with human liver microsomes mainly through C6 amide hydrolysis. Blocking of this metabolic hot spot led to discovery of 10 (CKD533) which is highly potent, selective and orally efficacious in conscious rabbit model for erectile dysfunction and now is undergoing preclinical toxicology study. 相似文献
18.
Noronha G Barrett K Boccia A Brodhag T Cao J Chow CP Dneprovskaia E Doukas J Fine R Gong X Gritzen C Gu H Hanna E Hood JD Hu S Kang X Key J Klebansky B Kousba A Li G Lohse D Mak CC McPherson A Palanki MS Pathak VP Renick J Shi F Soll R Splittgerber U Stoughton S Tang S Yee S Zeng B Zhao N Zhu H 《Bioorganic & medicinal chemistry letters》2007,17(3):602-608
We describe the identification of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine (3), a potent, orally active Src inhibitor with desirable PK properties, demonstrated activity in human tumor cell lines and in animal models of tumor growth. 相似文献
19.
André Giroux Louise Boulet Christine Brideau Anh Chau David Claveau Bernard Côté Diane Ethier Richard Frenette Marc Gagnon Jocelyne Guay Sébastien Guiral Joseph Mancini Evelyn Martins Frédéric Massé Nathalie Méthot Denis Riendeau Joel Rubin Daigen Xu Hongping Yu Yves Ducharme Richard W. Friesen 《Bioorganic & medicinal chemistry letters》2009,19(20):5837-5841
Phenanthrene imidazoles 26 and 44 have been identified as novel potent, selective and orally active mPGES-1 inhibitors. These inhibitors are significantly more potent than the previously reported chlorophenanthrene imidazole 1 (MF63) with a human whole blood IC50 of 0.20 and 0.14 μM, respectively. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model at oral doses as low as 14 mg/kg. Both active and selective mPGES-1 inhibitors (26 and 44) have a relatively distinct pharmacokinetic profile and are suitable for clinical development. 相似文献
20.
Paliwal S Reichard GA Shah S Wrobleski ML Wang C Stengone C Tsui HC Xiao D Duffy RA Lachowicz JE Nomeir AA Varty GB Shih NY 《Bioorganic & medicinal chemistry letters》2008,18(14):4168-4171
Strategic replacement of the nitrogen of the lead compound 1 in the original cyclic urea series with a carbon resulted in the discovery of a novel, potent and orally more efficacious γ-lactam series of selective NK1 antagonists. Optimization of the lactam series culminated in the identification of compounds with high binding affinity and excellent oral CNS activity. 相似文献