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

Summary for 3M6F

• Entry DOI: 10.2210/pdb3m6f/pdb
• Descriptor: 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)
• Functional Keywords: lfa1, inhibitor, alternative splicing, calcium, cell adhesion, disulfide bond, glycoprotein, integrin, magnesium, membrane, polymorphism, receptor, transmembrane
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane ; Single-pass type I membrane protein : P20701
• Total number of polymer chains: 1
• Total formula weight: 21534.35

Authors

Sheriff, S. (deposition date: 2010-03-15, release date: 2010-05-12, Last modification date: 2023-09-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.85 Å)