Crystal Structures of mPGES‑1 Inhibitor Complexes Form a Basis for the Rational Design of Potent Analgesic and Anti-Inflammatory Therapeutics

Microsomal prostaglandin E synthase 1 (mPGES-1) is an α-helical homotrimeric integral membrane inducible enzyme that catalyzes the formation of prostaglandin E₂ (PGE₂) from prostaglandin H₂ (PGH₂). Inhibition of mPGES-1 has been proposed as a therapeutic strategy for the treatment of pain, inflammation, and some cancers. Interest in mPGES-1 inhibition can, in part, be attributed to the potential circumvention of cardiovascular risks associated with anti-inflammatory cyclooxygenase 2 inhibitors (coxibs) by targeting the prostaglandin pathway downstream of PGH₂ synthesis and avoiding suppression of antithrombotic prostacyclin production. We determined the crystal structure of mPGES-1 bound to four potent inhibitors in order to understand their structure–activity relationships and provide a framework for the rational design of improved molecules. In addition, we developed a light-scattering-based thermal stability assay to identify molecules for crystallographic studies

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 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

Nonpeptidic ligands for peptide-activated G protein-coupled receptors

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