5BQI

Discovery of a Potent and Selective mPGES-1 Inhibitor for the Treatment of Pain

Summary for 5BQI

• Entry DOI: 10.2210/pdb5bqi/pdb
• Descriptor: Prostaglandin E synthase, 2-(difluoromethyl)-5-{[(2-methylpropanoyl)amino]methyl}-N-{5-methyl-4-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}pyridine-3-carboxamide, GLUTATHIONE, ... (7 entities in total)
• Functional Keywords: mpges-1, enzyme, integral membrane protein, targetname, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 18993.40

Authors

Fisher, M.J.,Schiffler, M.A.,Kuklish, S.L.,Antonysamy, S.,Luz, J.G. (deposition date: 2015-05-29, release date: 2016-04-13, Last modification date: 2024-03-06)

Primary citation

Schiffler, M.A.,Antonysamy, S.,Bhattachar, S.N.,Campanale, K.M.,Chandrasekhar, S.,Condon, B.,Desai, P.V.,Fisher, M.J.,Groshong, C.,Harvey, A.,Hickey, M.J.,Hughes, N.E.,Jones, S.A.,Kim, E.J.,Kuklish, S.L.,Luz, J.G.,Norman, B.H.,Rathmell, R.E.,Rizzo, J.R.,Seng, T.W.,Thibodeaux, S.J.,Woods, T.A.,York, J.S.,Yu, X.P.
Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors.
J.Med.Chem., 59:194-205, 2016

PubMed Abstract: As 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 μM. 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.

PubMed: 26653180
DOI: 10.1021/acs.jmedchem.5b01249

Experimental method

X-RAY DIFFRACTION (1.88 Å)