3M6F

CD11A I-domain complexed with 6-((5S,9R)-9-(4-CYANOPHENYL)-3-(3,5-DICHLOROPHENYL)-1-METHYL-2,4-DIOXO-1,3,7- TRIAZASPIRO[4.4]NON-7-YL)NICOTINIC ACID

3M6F の概要

• エントリーDOI: 10.2210/pdb3m6f/pdb
• 分子名称: Integrin alpha-L, 6-[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl]pyridine-3-carboxylic acid, NITRATE ION, ... (4 entities in total)
• 機能のキーワード: lfa1, inhibitor, alternative splicing, calcium, cell adhesion, disulfide bond, glycoprotein, integrin, magnesium, membrane, polymorphism, receptor, transmembrane
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cell membrane ; Single-pass type I membrane protein : P20701
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 21534.35

構造登録者

Sheriff, S. (登録日: 2010-03-15, 公開日: 2010-05-12, 最終更新日: 2023-09-06)

主引用文献

Watterson, S.H.,Xiao, Z.,Dodd, D.S.,Tortolani, D.R.,Vaccaro, W.,Potin, D.,Launay, M.,Stetsko, D.K.,Skala, S.,Davis, P.M.,Lee, D.,Yang, X.,McIntyre, K.W.,Balimane, P.,Patel, K.,Yang, Z.,Marathe, P.,Kadiyala, P.,Tebben, A.J.,Sheriff, S.,Chang, C.Y.,Ziemba, T.,Zhang, H.,Chen, B.C.,DelMonte, A.J.,Aranibar, N.,McKinnon, M.,Barrish, J.C.,Suchard, S.J.,Murali Dhar, T.G.
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-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)nicotinic acid (BMS-688521).
J.Med.Chem., 53:3814-3830, 2010

PubMed Abstract: Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or alpha(L)beta(2), belongs to the beta(2) 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.

PubMed: 20405922
DOI: 10.1021/jm100348u

実験手法

X-RAY DIFFRACTION (1.85 Å)