title: Discovery of 2-((2-chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1H-[1,4]dioxino[2',3':3,4]benzo[1,2-d]imidazole-5-carboxamide as potent, selective and efficacious microsomal prostaglandin E2synthase-1 (mPGES-1) inhibitor.
abstract: 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-1H-[1,4]dioxino[2',3':3,4]benzo[1,2-d]imidazole-5-carboxamide} exhibited excellent mPGES-1 enzyme (IC50: 8nM), cell (A549 IC50: 16.24nM) and human whole blood potency (IC50: 249.9nM). In rodent species, 17d strongly inhibited guinea pig mPGES-1 (IC50: 10.79nM), 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 ED50of 36.7mg/kg, respectively.
authors.affiliation: Chemical Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India.
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Muthukaman
authors.affiliation: Chemical Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Deshmukh
authors.affiliation: Chemical Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India.
authors.forename: Neelam
authors.initials: N
authors.lastname: Sarode
authors.affiliation: Chemical Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India.
authors.forename: Shital
authors.initials: S
authors.lastname: Tondlekar
authors.affiliation: Chemical Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India.
authors.forename: Macchindra
authors.initials: M
authors.lastname: Tambe
authors.affiliation: Chemical Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India.
authors.forename: Dnyandeo
authors.initials: D
authors.lastname: Pisal
authors.affiliation: Chemical Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India.
authors.forename: Mahamadhanif
authors.initials: M
authors.lastname: Shaikh
authors.affiliation: Biological Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India.
authors.forename: Vidya G
authors.initials: VG
authors.lastname: Kattige
authors.affiliation: Biological Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India.
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Honnegowda
authors.affiliation: Biological Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Karande
authors.affiliation: Biological Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India.
authors.forename: Abhay
authors.initials: A
authors.lastname: Kulkarni
authors.affiliation: Drug Metabolism and Pharmacokinetics, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India.
authors.forename: Satyawan B
authors.initials: SB
authors.lastname: Jadhav
authors.affiliation: Drug Metabolism and Pharmacokinetics, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India.
authors.forename: Mahamad Yunnus A
authors.initials: MYA
authors.lastname: Mahat
authors.affiliation: Drug Metabolism and Pharmacokinetics, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India.
authors.forename: Girish S
authors.initials: GS
authors.lastname: Gudi
authors.affiliation: Biological Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India.
authors.forename: Neelima
authors.initials: N
authors.lastname: Khairatkar-Joshi
authors.affiliation: Chemical Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India. Electronic address: Laxmikant.gharat@glenmarkpharma.com.
authors.forename: Laxmikant A
authors.initials: LA
authors.lastname: Gharat
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004146:Dioxanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D006358:Hot Temperature; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy*; D000071876:Prostaglandin-E Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C000620861:2-((2-chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1H-(1,4)dioxino(2',3'-3,4)benzo(1,2-d)imidazole-5-carboxamide; D001562:Benzimidazoles; D004146:Dioxanes; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D000071876:Prostaglandin-E Synthases
keywords: Benzimidazole; CSF concentration; PGE(2); Rheumatoid arthritis; Scaffold hopping; mPGES-1 inhibitor