Identification and Mitigation of Reactive Metabolites of 2‑Aminoimidazole-Containing Microsomal Prostaglandin E Synthase‑1 Inhibitors Terminated Due to Clinical Drug-Induced Liver Injury

Two 2-aminoimidazole-based inhibitors, LY3031207 (<b>1</b>) and LY3023703 (<b>2</b>), of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme were found to cause drug-induced liver injury (DILI) in humans. We studied imidazole ring substitutions to successfully mitigate reactive metabolite (RM) formation. These studies support the conclusion that RM formation may play a role in the observations of DILI and the consideration of 2-aminoimidazoles as structure alerts, due to the high likelihood of bioactivation to generate RMs

Identification and Mitigation of Reactive Metabolites of 2‑Aminoimidazole-Containing Microsomal Prostaglandin E Synthase‑1 Inhibitors Terminated Due to Clinical Drug-Induced Liver Injury

Two 2-aminoimidazole-based inhibitors, LY3031207 (<b>1</b>) and LY3023703 (<b>2</b>), of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme were found to cause drug-induced liver injury (DILI) in humans. We studied imidazole ring substitutions to successfully mitigate reactive metabolite (RM) formation. These studies support the conclusion that RM formation may play a role in the observations of DILI and the consideration of 2-aminoimidazoles as structure alerts, due to the high likelihood of bioactivation to generate RMs

Novel Autotaxin Inhibitors for the Treatment of Osteoarthritis Pain: Lead Optimization via Structure-Based Drug Design

In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC₅₀ of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstrated favorable potency (IC₅₀ = 2 nM), PK properties, and a robust PK/PD relationship

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