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

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 (<i>m</i>PGES-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 <b>8</b>, which had desirable potency (IC₅₀ = 12 nM in an <i>ex vivo</i> human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Studies on the formulation of <b>8</b> identified <b>8·H</b>_<b>3</b><b>PO</b>_<b>4</b> as suitable for clinical development. Omission of a lipophilic portion of the compound led to <b>26</b>, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, <b>26</b> was selective for <i>m</i>PGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of <b>26</b> as a second clinical candidate