Design of LFA-1 antagonists based on a 2,3-dihydro-1H-pyrrolizin-5(7aH)-one scaffold

Dharmpal S Dodd; Steven Sheriff; ChiehYing J Chang; Dawn K Stetsko; Linda M Phillips; Yingru Zhang; Michele Launay; Dominique Potin; Wayne Vaccaro; Michael A Poss; Murray McKinnon; Joel C Barrish; Suzanne J Suchard; T G Murali Dhar

doi:10.1016/j.bmcl.2007.01.036

Design of LFA-1 antagonists based on a 2,3-dihydro-1H-pyrrolizin-5(7aH)-one scaffold

Bioorg Med Chem Lett. 2007 Apr 1;17(7):1908-11. doi: 10.1016/j.bmcl.2007.01.036. Epub 2007 Jan 24.

Authors

Dharmpal S Dodd¹, Steven Sheriff, ChiehYing J Chang, Dawn K Stetsko, Linda M Phillips, Yingru Zhang, Michele Launay, Dominique Potin, Wayne Vaccaro, Michael A Poss, Murray McKinnon, Joel C Barrish, Suzanne J Suchard, T G Murali Dhar

Affiliation

¹ Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, NJ 08543-4000, USA. [email protected]

PMID: 17291752
DOI: 10.1016/j.bmcl.2007.01.036

Abstract

A new class of lymphocyte function-associated antigen-1 (LFA-1) antagonists is described. Elaboration of the 2,3-dihydro-1H-pyrrolizin-5(7aH)-one scaffold resulted in the synthesis of potent inhibitors of the LFA-1/ICAM-1 interaction. Along with the in vitro activity, we present the X-ray crystal structure of the complex of compound 9b, in a novel binding mode to the I-domain of LFA-1.

MeSH terms

Chemistry, Pharmaceutical / methods*
Crystallography, X-Ray
Drug Design
Drug Screening Assays, Antitumor
HeLa Cells
Humans
Inhibitory Concentration 50
Lymphocyte Function-Associated Antigen-1 / chemistry*
Models, Chemical
Molecular Conformation
Pyrroles / chemistry*
Stereoisomerism
Temperature
X-Rays

Substances

Lymphocyte Function-Associated Antigen-1
Pyrroles