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

J Med Chem. 2016 Jan 14;59(1):194-205. doi: 10.1021/acs.jmedchem.5b01249.

Matthew A Schiffler ¹, Stephen Antonysamy ², Shobha N Bhattachar ¹, Kristina M Campanale ¹, Srinivasan Chandrasekhar ¹, Bradley Condon ², Prashant V Desai ¹, Matthew J Fisher ¹, Christopher Groshong ², Anita Harvey ¹, Michael J Hickey ², Norman E Hughes ¹, Scott A Jones ¹, Euibong J Kim ¹, Steven L Kuklish ¹, John G Luz ², Bryan H Norman ¹, Richard E Rathmell ³, John R Rizzo ¹, Thomas W Seng ¹, Stefan J Thibodeaux ¹, Timothy A Woods ¹, Jeremy S York ¹, Xiao-Peng Yu ¹

Affiliations

1 Lilly Research Laboratories, A Division of Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
2 Eli Lilly Biotechnology Center , San Diego, California 92121, United States.
3 Lilly Research Laboratories, A Division of Eli Lilly and Company , Windlesham, Surrey GU20 6PH, United Kingdom.

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

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.

Name
Email *

	Sorry, but the email address you supplied was invalid.