title: 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.
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.
authors.affiliation: Cerep, 19 avenue du Quebec, 91951 Courtaboeuf cedex, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Potin
authors.forename: Michele
authors.initials: M
authors.lastname: Launay
authors.forename: Francoise
authors.initials: F
authors.lastname: Monatlik
authors.forename: Patrice
authors.initials: P
authors.lastname: Malabre
authors.forename: Maud
authors.initials: M
authors.lastname: Fabreguettes
authors.forename: Andre
authors.initials: A
authors.lastname: Fouquet
authors.forename: Magali
authors.initials: M
authors.lastname: Maillet
authors.forename: Eric
authors.initials: E
authors.lastname: Nicolai
authors.forename: Loïc
authors.initials: L
authors.lastname: Dorgeret
authors.forename: François
authors.initials: F
authors.lastname: Chevallier
authors.forename: Dominique
authors.initials: D
authors.lastname: Besse
authors.forename: Monique
authors.initials: M
authors.lastname: Dufort
authors.forename: François
authors.initials: F
authors.lastname: Caussade
authors.forename: Syed Z
authors.initials: SZ
authors.lastname: Ahmad
authors.forename: Dawn K
authors.initials: DK
authors.lastname: Stetsko
authors.forename: Stacey
authors.initials: S
authors.lastname: Skala
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Davis
authors.forename: Praveen
authors.initials: P
authors.lastname: Balimane
authors.forename: Karishma
authors.initials: K
authors.lastname: Patel
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Punit
authors.initials: P
authors.lastname: Marathe
authors.forename: Jennifer
authors.initials: J
authors.lastname: Postelneck
authors.forename: Robert M
authors.initials: RM
authors.lastname: Townsend
authors.forename: Valentina
authors.initials: V
authors.lastname: Goldfarb
authors.forename: Steven
authors.initials: S
authors.lastname: Sheriff
authors.forename: Howard
authors.initials: H
authors.lastname: Einspahr
authors.forename: Kevin
authors.initials: K
authors.lastname: Kish
authors.forename: Mary F
authors.initials: MF
authors.lastname: Malley
authors.forename: John D
authors.initials: JD
authors.lastname: DiMarco
authors.forename: Jack Z
authors.initials: JZ
authors.lastname: Gougoutas
authors.forename: Pathanjali
authors.initials: P
authors.lastname: Kadiyala
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Cheney
authors.forename: Ravindra W
authors.initials: RW
authors.lastname: Tejwani
authors.forename: Denette K
authors.initials: DK
authors.lastname: Murphy
authors.forename: Kim W
authors.initials: KW
authors.lastname: Mcintyre
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Yang
authors.forename: Sam
authors.initials: S
authors.lastname: Chao
authors.forename: Leslie
authors.initials: L
authors.lastname: Leith
authors.forename: Zili
authors.initials: Z
authors.lastname: Xiao
authors.forename: Arvind
authors.initials: A
authors.lastname: Mathur
authors.forename: Bang-Chi
authors.initials: BC
authors.lastname: Chen
authors.forename: Daugh-Rurng
authors.initials: DR
authors.lastname: Wu
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Traeger
authors.forename: Murray
authors.initials: M
authors.lastname: McKinnon
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Robl
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Iwanowicz
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Suchard
authors.forename: T G Murali
authors.initials: TG
authors.lastname: Dhar
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D018360:Crystallography, X-Ray; D004285:Dogs; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011014:Pneumonia / Q000188:drug therapy / Q000276:immunology; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014184:Transplantation, Homologous
chemical_list: C517055:5-(9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro(4,4)non-7-ylmethyl)-3-thiophenecarboxylic acid; D016169:Lymphocyte Function-Associated Antigen-1; D013141:Spiro Compounds; D013876:Thiophenes