2. Academic Validation
  3. Discovery of novel and potent leukotriene B4 receptor antagonists. Part 1

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

  • J Med Chem. 2010 May 13;53(9):3502-16. doi: 10.1021/jm1001919.
Robert A Goodnow Jr 1,  Alexandra Hicks,  Achyutharao Sidduri,  Agnieszka Kowalczyk,  Romyr Dominique,  Qi Qiao,  Jian Ping Lou,  Paul Gillespie,  Nader Fotouhi,  Jefferson Tilley,  Noal Cohen,  Satish Choudhry,  Gary Cavallo,  Shahid A Tannu,  Jessica D Ventre,  Danielle Lavelle,  Nadine S Tare,  Hyesun Oh,  Martin Lamb,  Grazyna Kurylko,  Rachid Hamid,  Matthew B Wright,  Anjula Pamidimukkala,  Thomas Egan,  Ueli Gubler,  Ann F Hoffman,  Xin Wei,  Ying L Li,  John O'Neil,  Ruben Marcano,  Karen Pozzani,  Tina Molinaro,  Jennifer Santiago,  Laura Singer,  Maureen Hargaden,  David Moore,  A Robert Catala,  Lisa C F Chao,  Gesine Hermann,  Radhika Venkat,  Helena Mancebo,  Louis M Renzetti
Affiliations

Affiliation

  • 1 Department of Discovery Chemistry, Roche Research Center, 340 Kingsland Street, Nutley, New Jersey 07110-1199, USA. [email protected]
PMID: 20380377 DOI: 10.1021/jm1001919
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.

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