1. Discovery of Novel and Potent Leukotriene B4 Receptor Antagonists. Part 1
- Author
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Tina Molinaro, Robert Alan Goodnow, Louis M. Renzetti, Alexandra Hicks, Satish Choudhry, Xin Wei, Gesine J. Hermann, Qi Qiao, Anjula Pamidimukkala, A. Robert Catala, Maureen Hargaden, Jian Ping Lou, Nadine Tare, John O’Neil, Ueli Gubler, Karen Pozzani, David J Moore, Jennifer Santiago, Ruben Marcano, Paul Gillespie, Rachid Hamid, Noal Cohen, Hyesun Oh, Lisa C. F. Chao, Laura Singer, Jefferson Wright Tilley, Romyr Dominique, Grazyna Kurylko, Ying L. Li, Radhika Venkat, Achyutharao Sidduri, Matthew Blake Wright, Ann F. Hoffman, Shahid Tannu, Gary Cavallo, Nader Fotouhi, Thomas Egan, Martin Lamb, Jessica D. Ventre, Agnieszka Kowalczyk, D Lavelle, and Helena Mancebo
- Subjects
Primates ,Leukotriene B4 ,medicine.drug_class ,Guinea Pigs ,Drug Evaluation, Preclinical ,Receptors, Leukotriene B4 ,HL-60 Cells ,Pharmacology ,Receptors, G-Protein-Coupled ,Guinea pig ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,medicine ,Animals ,Humans ,Receptor ,ADME ,Chemistry ,Phenyl Ethers ,Leukotriene B4 receptor ,Receptor antagonist ,In vitro ,Rats ,Bioavailability ,Biochemistry ,Leukotriene Antagonists ,Molecular Medicine ,Protein Binding - 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.
- Published
- 2010
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