5bqi | pdb_00005bqi
Discovery of a Potent and Selective mPGES-1 Inhibitor for the Treatment of Pain
Structural highlights
FunctionPTGES_HUMAN Catalyzes the oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2).[1] Publication Abstract from PubMedAs part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 17.4 muM. Structural information was used to improve enzyme potency by over 1000-fold. Addition of an appropriate substituent alleviated time-dependent cytochrome P450 3A4 (CYP3A4) inhibition. Further structure-activity relationship (SAR) studies led to 8, which had desirable potency (IC50 = 12 nM in an ex vivo human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Studies on the formulation of 8 identified 8.H3PO4 as suitable for clinical development. Omission of a lipophilic portion of the compound led to 26, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, 26 was selective for mPGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of 26 as a second clinical candidate. Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors.,Schiffler MA, Antonysamy S, Bhattachar SN, Campanale KM, Chandrasekhar S, Condon B, Desai PV, Fisher MJ, Groshong C, Harvey A, Hickey MJ, Hughes NE, Jones SA, Kim EJ, Kuklish SL, Luz JG, Norman BH, Rathmell RE, Rizzo JR, Seng TW, Thibodeaux SJ, Woods TA, York JS, Yu XP J Med Chem. 2016 Jan 14;59(1):194-205. doi: 10.1021/acs.jmedchem.5b01249. Epub, 2015 Dec 18. PMID:26653180[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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