4 research outputs found
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 IC<sub>50</sub> of 500 nM. X-ray crystallography enabled the optimization to a lead
compound that demonstrated favorable potency (IC<sub>50</sub> = 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 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