2. Academic Validation
  3. Identification and biological activity of 6-alkyl-substituted 3-methyl-pyridine-2-carbonyl amino dimethyl-benzoic acid EP4 antagonists

Identification and biological activity of 6-alkyl-substituted 3-methyl-pyridine-2-carbonyl amino dimethyl-benzoic acid EP4 antagonists

  • Bioorg Med Chem Lett. 2016 May 1;26(9):2303-7. doi: 10.1016/j.bmcl.2016.03.041.
Maria-Jesus Blanco 1,  Tatiana Vetman 2,  Srinivasan Chandrasekhar 2,  Matthew J Fisher 2,  Anita Harvey 2,  Steven L Kuklish 2,  Mark Chambers 2,  Chaohua Lin 2,  Daniel Mudra 2,  Jennifer Oskins 2,  Xu-Shan Wang 2,  Xiao-Peng Yu 2,  Alan M Warshawsky 2
Affiliations

Affiliations

  • 1 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States. Electronic address: blanco_maria@lilly.com.
  • 2 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
PMID: 27020304 DOI: 10.1016/j.bmcl.2016.03.041
Abstract

Continued SAR optimization of a series of 3-methylpyridine-2-carbonyl amino-2,4-dimethyl-benzoic acid led to the selection of compound 4f for clinical studies. Compound 4f showed an IC50 of 123nM for inhibition of PGE2-induced TNFα reduction in an ex vivo LPS-stimulated human whole blood assay (showing >10-fold increase over clinical compound CJ-023,423). Pharmacokinetic profile, selectivity and in vivo efficacy comparing 4f to NSAID diclofenac in the monoiodoacetic acid (MIA) pain model and Adjuvant induced arthritis (AIA) inflammatory model are included.

Keywords

Clinical candidate; EP4 antagonist; Inflammation; Pain; Prostaglandin E2 (PGE2).

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