| Literature DB >> 26653180 |
Matthew A Schiffler1, Stephen Antonysamy2, Shobha N Bhattachar1, Kristina M Campanale1, Srinivasan Chandrasekhar1, Bradley Condon2, Prashant V Desai1, Matthew J Fisher1, Christopher Groshong2, Anita Harvey1, Michael J Hickey2, Norman E Hughes1, Scott A Jones1, Euibong J Kim1, Steven L Kuklish1, John G Luz2, Bryan H Norman1, Richard E Rathmell3, John R Rizzo1, Thomas W Seng1, Stefan J Thibodeaux1, Timothy A Woods1, Jeremy S York1, Xiao-Peng Yu1.
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.Entities:
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Year: 2015 PMID： 26653180 DOI： 10.1021/acs.jmedchem.5b01249
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446