文摘
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 ICb>50b> 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>8b>, which had desirable potency (ICb>50b> = 12 nM in an ex vivo human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Studies on the formulation of <b>8b> identified <b>8·Hb>b><b>3b>b><b>POb>b><b>4b>b> as suitable for clinical development. Omission of a lipophilic portion of the compound led to <b>26b>, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, <b>26b> was selective for mPGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of <b>26b> as a second clinical candidate.