1 research outputs found
Discovery and Characterization of 2‑Acylaminoimidazole Microsomal Prostaglandin E Synthase‑1 Inhibitors
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 IC<sub>50</sub> 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 (IC<sub>50</sub> = 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><sub><b>3</b></sub><b>PO</b><sub><b>4</b></sub> 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