Small Molecule Antagonist of Leukocyte Function Associated Antigen-1 (LFA-1): Structure−Activity Relationships Leading to the Identification of 6-((5S,9R)-9-(4-Cyanophenyl)-3-(3,5-

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• 作者：Scott H. Watterson ; Zili Xiao ; Dharmpal S. Dodd ; David R. Tortolani ; Wayne Vaccaro ; Dominique Potin ; Michele Launay ; Dawn K. Stetsko ; Stacey Skala ; Patric M. Davis ; Deborah Lee ; Xiaoxia Yang ; Kim W. M
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：May 13, 2010
• 年：2010
• 卷：53
• 期：9
• 页码：3814-3830
• 全文大小：1222K
• 年卷期：v.53,no.9(May 13, 2010)
• ISSN：1520-4804

文摘

Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or α_Lβ₂, belongs to the β₂ integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion molecules 1, 2, and 3 (ICAM 1, 2, and 3). The interactions between LFA-1 and the ICAMs are critical for cell adhesion, and preclinical animal studies and clinical data from the humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept for LFA-1 as an immunological target. This article will detail the structure−activity relationships (SAR) leading to a novel second generation series of highly potent spirocyclic hydantoin antagonists of LFA-1. With significantly enhanced in vitro and ex vivo potency relative to our first clinical compound (1), as well as demonstrated in vivo activity and an acceptable pharmacokinetic and safety profile, 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro-[4.4]nonan-7-yl)nicotinic acid (2e) was selected to advance into clinical trials.