title: Development of 2-aryl substituted quinazolin-4(3H)-one, pyrido[4,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as microsomal prostaglandin E(2) synthase-1 inhibitors.
abstract: mPGES-1 is inducible terminal synthase acting downstream of COX enzymes in arachidonic acid pathway, regulates the biosynthesis of pro-inflammatory prostaglandin PGE2. Cardiovascular side effect of coxibs and NSAIDs, selective for COX-2 inhibition, stimulated interest in mPGES-1, a therapeutic target with potential to deliver safe and effective anti-inflammatory drugs. The synthesis and structure activity relationship of a series of compounds from 2-aryl substituted quinazolin-4(3H)-one, pyrido[4,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one scaffolds as mPGES-1 inhibitor are discussed. A set of analogs (28, 48, 49) were identified with <10nM potencies in the recombinant human mPGES-1 enzyme and in the A549 cellular assays. These analogs were also found to be potent in the human whole blood assay (<400 nM). Furthermore, the representative compound 48 was shown to be selective with other prostanoid synthases and was able to effectively regulate PGE2 biosynthesis in clinically relevant inflammatory settings, in comparison with celecoxib.
authors.affiliation: Glenmark Pharmaceuticals Limited, Navi Mumbai 400709, Maharashtra, India.
authors.forename: Abhisek
authors.initials: A
authors.lastname: Banerjee
authors.affiliation: Glenmark Pharmaceuticals Limited, Navi Mumbai 400709, Maharashtra, India.
authors.forename: Mahesh Y
authors.initials: MY
authors.lastname: Pawar
authors.affiliation: Glenmark Pharmaceuticals Limited, Navi Mumbai 400709, Maharashtra, India.
authors.forename: Sandip
authors.initials: S
authors.lastname: Patil
authors.affiliation: Glenmark Pharmaceuticals Limited, Navi Mumbai 400709, Maharashtra, India.
authors.forename: Pravin S
authors.initials: PS
authors.lastname: Yadav
authors.affiliation: Glenmark Pharmaceuticals Limited, Navi Mumbai 400709, Maharashtra, India.
authors.forename: Pradip A
authors.initials: PA
authors.lastname: Kadam
authors.affiliation: Glenmark Pharmaceuticals Limited, Navi Mumbai 400709, Maharashtra, India.
authors.forename: Vidya G
authors.initials: VG
authors.lastname: Kattige
authors.affiliation: Glenmark Pharmaceuticals Limited, Navi Mumbai 400709, Maharashtra, India.
authors.forename: Durga S
authors.initials: DS
authors.lastname: Deshpande
authors.affiliation: Glenmark Pharmaceuticals Limited, Navi Mumbai 400709, Maharashtra, India.
authors.forename: Pallavi V
authors.initials: PV
authors.lastname: Pednekar
authors.affiliation: Glenmark Pharmaceuticals Limited, Navi Mumbai 400709, Maharashtra, India.
authors.forename: Monali K
authors.initials: MK
authors.lastname: Pisat
authors.affiliation: Glenmark Pharmaceuticals Limited, Navi Mumbai 400709, Maharashtra, India. Electronic address: laxmikant_gharat@glenmarkpharma.com.
authors.forename: Laxmikant A
authors.initials: LA
authors.lastname: Gharat
mesh_terms: D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D000071876:Prostaglandin-E Synthases; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011744:Pyrimidinones; D052999:Quinazolinones; C582693:pyrido(4,3-d)pyrimidin-4(3H)-one; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases
keywords: Analgesic; Cyclooxygenase; Prostaglandin E(2); Quinazolinone; mPGES-1