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

  • J Med Chem. 2006 Nov 30;49(24):6946-9. doi: 10.1021/jm0610806.
Dominique Potin  1 ,  Michele Launay ,  Francoise Monatlik ,  Patrice Malabre ,  Maud Fabreguettes ,  Andre Fouquet ,  Magali Maillet ,  Eric Nicolai ,  Loïc Dorgeret ,  François Chevallier ,  Dominique Besse ,  Monique Dufort ,  François Caussade ,  Syed Z Ahmad ,  Dawn K Stetsko ,  Stacey Skala ,  Patricia M Davis ,  Praveen Balimane ,  Karishma Patel ,  Zheng Yang ,  Punit Marathe ,  Jennifer Postelneck ,  Robert M Townsend ,  Valentina Goldfarb ,  Steven Sheriff ,  Howard Einspahr ,  Kevin Kish ,  Mary F Malley ,  John D DiMarco ,  Jack Z Gougoutas ,  Pathanjali Kadiyala ,  Daniel L Cheney ,  Ravindra W Tejwani ,  Denette K 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
Affiliations
  • 1. Cerep, 19 avenue du Quebec, 91951 Courtaboeuf cedex, France.
PMID: 17125246 DOI: 10.1021/jm0610806
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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