Discovery and Development of 5-[(5S,9R)-9- (4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1- methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non- 7-yl-methyl]-3-thiophenecarboxylic Acid (BMS-587101)A Small Molecule Antagonist of Leukocyte Function Associated Antigen-1
Journal of Medicinal Chemistry2006Vol. 49(24), pp. 6946–6949
Citations Over TimeTop 22% of 2006 papers
Dominique Potin, Michèle Launay, Francoise Monatlik, Patrice Malabre, Maud Fabreguettes, Andre Fouquet, Magali Maillet, Eric Nicolaï, Loïc Dorgeret, F Chevallier, Dominique Besse, Monique Dufort, F. Caussade, Syed Zain Ahmad, Dawn K. Stetsko, Stacey Skala, Patricia M. Davis, Praveen Balimane, Karishma Patel, Zheng Yang, Punit Marathe, Jennifer Postelneck, Robert M. Townsend, Valentina Goldfarb, S. Sheriff, Howard Einspahr, Kevin Kish, Mary F. Malley, John D. DiMarco, Jack Z. Gougoutas, Pathanjali Kadiyala, Daniel L. Cheney, Ravindra W. Tejwani, Denette Murphy, Kim W. McIntyre, Xiaoxia Yang, Sam Chao, Leslie Leith, Zili Xiao, Arvind Mathur, Bang‐Chi Chen, Daugh-Rurng Wu, Sarah C. Traeger, Murray McKinnon, Joel C. Barrish, Jeffrey A. Robl, Edwin J. Iwanowicz, Suzanne J. Suchard, T. G. Murali Dhar
Abstract
LFA-1 (leukocyte function-associated antigen-1), is a member of the beta2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.
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