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Title: Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors

Journal Article · · Journal of Medicinal Chemistry
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  1. Lilly Research Labs, Indianapolis, IN (United States)
  2. Eli Lilly Biotechnology Center, San Diego, CA (United States)
  3. Lilly Research Labs, Surrey (United Kingdom)
+ Show Author Affiliations

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 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 8, which had desirable potency (IC50 = 12 nM in an ex vivo human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Here, studies on the formulation of 8 identified 8·H3PO4 as suitable for clinical development. Omission of a lipophilic portion of the compound led to 26, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, 26 was selective for mPGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of 26 as a second clinical candidate.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1240190
Journal Information:
Journal of Medicinal Chemistry, Vol. 59, Issue 1; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 44 works
Citation information provided by
Web of Science

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Cited By (6)

Ruthenium-Catalyzed meta -Selective C−H Mono- and Difluoromethylation of Arenes through ortho -Metalation Strategy journal February 2017
Discovery of 3-hydroxy-3-pyrrolin-2-one-based mPGES-1 inhibitors using a multi-step virtual screening protocol journal January 2018
Nonsteroidal Anti-Inflammatory Therapy: A Journey Toward Safety: A JOURNEY IN NONSTEROIDAL ANTI-INFLAMMATORY THERAPY journal December 2016
How the dual PDZ domain from Postsynaptic density protein 95 clusters ion channels and receptors preprint September 2019
Microsomal prostaglandin E 2 synthase-1 inhibitors: a patent review journal June 2017
Discovery of a celecoxib binding site on PTGES with a cleavable chelation-assisted biotin probe preprint September 2019

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
assays
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