Literature

Abstract

Here we report on novel, potent 3,3-dimethyl substituted N-aryl piperidine inhibitors of microsomal prostaglandin E synthases-1(mPGES-1). Example 14 potently inhibited PGE2 synthesis in an ex vivo human whole blood (HWB) assay with an IC50 of 7nM. In addition, 14 had no activity in human COX-1 or COX-2 assays at 30μM, and failed to inhibit human mPGES-2 at 62.5μM in a microsomal prep assay. These data are consistent with selective mPGES-1-mediated reduction of PGE2. In dog, 14 had oral bioavailability (74%), clearance (3.62mL/(min*kg)) and volume of distribution (Vd,ss=1.6L/kg) values within our target ranges. For these reasons, 14 was selected for further study.

DOI： 10.1016/j.bmcl.2016.08.023

Characterization of 3,3-dimethyl substituted N-aryl piperidines as potent microsomal prostaglandin E synthase-1 inhibitors

Bioorganic & Medicinal Chemistry Letters 2016.0

Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors

Journal of Medicinal Chemistry 2016.0

Discovery of Highly Potent Microsomal Prostaglandin E2 Synthase 1 Inhibitors Using the Active Conformation Structural Model and Virtual Screen

Journal of Medicinal Chemistry 2013.0

Tricyclic 4,4-dimethyl-3,4-dihydrochromeno[3,4- d ]imidazole derivatives as microsomal prostaglandin E 2 synthase-1 (mPGES-1) inhibitors: SAR and in vivo efficacy in hyperalgesia pain model

Bioorganic & Medicinal Chemistry Letters 2017.0

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

Bioorganic & Medicinal Chemistry Letters 2016.0

Structure–Activity Relationship of Nonacidic Quinazolinone Inhibitors of Human Microsomal Prostaglandin Synthase 1 (mPGES 1)