Discovery of 2-((2-chloro-6-fluorophenyl)amino)- N -(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1 H -[1,4]dioxino[2′,3′:3,4]benzo[1,2- d ]imidazole-5-carboxamide as potent, selective and efficacious microsomal prostaglandin E 2 synthase-1 (mPGES-1) inhibitor
| Autor: | Satyawan Jadhav, Mahamadhanif S. Shaikh, Abhay Kulkarni, Mahamad Yunnus A. Mahat, Nagarajan Muthukaman, Srinivasa Honnegowda, Vidya Ganapati Kattige, Laxmikant Atmaram Gharat, Vikas Karande, Shital Tondlekar, Dnyandeo Pisal, Macchindra Tambe, Neelima Khairatkar-Joshi, Girish S. Gudi, Neelam Sarode, Sanjay Deshmukh |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Benzimidazole medicine.drug_class Stereochemistry Clinical Biochemistry Pharmaceutical Science Carboxamide 01 natural sciences Biochemistry Guinea pig 03 medical and health sciences chemistry.chemical_compound In vivo Drug Discovery medicine Imidazole Molecular Biology chemistry.chemical_classification Trifluoromethyl 010405 organic chemistry Organic Chemistry 0104 chemical sciences 030104 developmental biology Enzyme chemistry Microsome Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 26:5977-5984 |
| ISSN: | 0960-894X |
| Popis: | The discovery and SAR of potent, selective dioxane-fused tricyclic benz[ d ]imidazole derivatives as mPGES-1 inhibitor are herein described. Various amide modifications in this series afforded many potent mPGES-1 inhibitors, of which 17d proved to be suitable for further profiling in vivo . Compound 17d {2-((2-chloro-6-fluorophenyl)amino)- N -(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1 H -[1,4]dioxino[2′,3′:3,4]benzo[1,2- d ]imidazole-5-carboxamide} exhibited excellent mPGES-1 enzyme (IC 50 : 8 nM), cell (A549 IC 50 : 16.24 nM) and human whole blood potency (IC 50 : 249.9 nM). In rodent species, 17d strongly inhibited guinea pig mPGES-1 (IC 50 : 10.79 nM), but not the rat and mouse enzyme. Furthermore 17d displayed excellent in vitro selectivity over mPGES-2, cPGES, COX-enzymes (COX-1, 2), selectivity against other prostanoid synthases, favorable hERG and CEREP panel profile. Likewise, our lead 17d demonstrated good oral pharmacokinetic profiles and good CNS B/P ratio in rat and guinea pig. Lead 17d also unveiled good efficacy in LPS-induced thermal hyperalgesia pain model with ED 50 of 36.7 mg/kg, respectively. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect