Document Report Card

ID: ALA1158546

Journal: J Med Chem

Title: Discovery of novel and potent leukotriene B4 receptor antagonists. Part 1.

Authors: Goodnow RA, Hicks A, Sidduri A, Kowalczyk A, Dominique R, Qiao Q, Lou JP, Gillespie P, Fotouhi N, Tilley J, Cohen N, Choudhry S, Cavallo G, Tannu SA, Ventre JD, Lavelle D, Tare NS, Oh H, Lamb M, Kurylko G, Hamid R, Wright MB, Pamidimukkala A, Egan T, Gubler U, Hoffman AF, Wei X, Li YL, O'Neil J, Marcano R, Pozzani K, Molinaro T, Santiago J, Singer L, Hargaden M, Moore D, Catala AR, Chao LC, Hermann G, Venkat R, Mancebo H, Renzetti LM.

Abstract: The inhibition of LTB(4) binding to and activation of G-protein-coupled receptors BLT1 and BLT2 is the premise of a treatment for several inflammatory diseases. In a lead optimization effort starting with the leukotriene B(4) (LTB(4)) receptor antagonist (2), members of a series of 3,5-diarylphenyl ethers were found to be highly potent inhibitors of LTB(4) binding to BLT1 and BLT2 receptors, with varying levels of selectivity depending on the substitution. In addition, compounds 33 and 38 from this series have good in vitro ADME properties, good oral bioavailability, and efficacy after oral delivery in guinea pig LTB(4) and nonhuman primate allergen challenge models. Further profiling in a rat non-GLP toxicity experiment provided the rationale for differentiation and selection of one compound (33) for clinical development.

CiteXplore: 20380377

DOI: 10.1021/jm1001919