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

Citation:
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.
PDB ID: 3M6FDownload
MMDB ID: 82054
PDB Deposition Date: 2010/3/15
Updated in MMDB: 2011/05
Experimental Method:
x-ray diffraction
Resolution: 1.85  Å
Source Organism:
Similar Structures:
Biological Unit for 3M6F: monomeric; determined by author and by software (PISA)
Molecular Components in 3M6F
Label Count Molecule
Protein (1 molecule)
1
Integrin Alpha-l(Gene symbol: ITGAL)
Molecule annotation
Chemicals (2 molecules)
1
1
2
1
* Click molecule labels to explore molecular sequence information.

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