title: Tricyclic 4,4-dimethyl-3,4-dihydrochromeno[3,4-d]imidazole derivatives as microsomal prostaglandin E2synthase-1 (mPGES-1) inhibitors: SAR and in vivo efficacy in hyperalgesia pain model.
abstract: A series of substituted tricyclic 4,4-dimethyl-3,4-dihydrochromeno[3,4-d]imidazole derivatives have been synthesized and their mPGES-1 biological activity has been disclosed in detail. Structure-activity relationship (SAR) optimization provided inhibitors with excellent mPGES-1 potency and low to moderate PGE2release A549 cell potency. Among the mPGES-1 inhibitors studied, 7, 9 and 11l provided excellent selectivity over COX-2 (>200-fold) and >70-fold selectivity for COX-1 except 11l, which exhibited dual mPGES-1/COX-1 activity. Furthermore, the above tested mPGES-1 inhibitors demonstrated good metabolic stability in liver microsomes, high plasma protein binding (PPB) and no significant inhibition observed in clinically relevant CYP isoforms. Besides, selected mPGES-1 tool compounds 9 and 11l provided good in vivo pharmacokinetic profile and oral bioavailability (%F=33 and 85). Additionally, the representative mPGES-1 tool compounds 9 and 11l revealed moderate in vivo efficacy in the LPS-induced thermal hyperalgesia guinea pig pain model.
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: Macchindra
authors.initials: M
authors.lastname: Tambe
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: 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: Sanjay
authors.initials: S
authors.lastname: Deshmukh
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: Neelam
authors.initials: N
authors.lastname: Sarode
authors.affiliation: Chemical Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India.
authors.forename: Lakshminarayana
authors.initials: L
authors.lastname: Narayana
authors.affiliation: Chemical Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India.
authors.forename: Jitendra M
authors.initials: JM
authors.lastname: Gajera
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: Dayanidhi
authors.initials: D
authors.lastname: Behera
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: 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: D000072283:A549 Cells; D000284:Administration, Oral; D000818:Animals; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D006168:Guinea Pigs; D006207:Half-Life; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D000071876:Prostaglandin-E Synthases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone
keywords: Arachidonic acid; Aryl imidazole; Hyperalgesia; PGE(2); Rheumatoid arthritis; mPGES-1 inhibitor