2. Academic Validation
  3. 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

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

Affiliation

  • 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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