Second-generation lymphocyte function-associated antigen-1 inhibitors: 1H-imidazo[1,2-alpha]imidazol-2-one derivatives

  • J Med Chem. 2004 Oct 21;47(22):5356-66. doi: 10.1021/jm049657b.
Jiang-Ping Wu  1 ,  Jonathan Emeigh ,  Donghong A Gao ,  Daniel R Goldberg ,  Daniel Kuzmich ,  Clara Miao ,  Ian Potocki ,  Kevin C Qian ,  Ronald J Sorcek ,  Deborah D Jeanfavre ,  Kei Kishimoto ,  Elizabeth A Mainolfi ,  Gerald Nabozny Jr ,  Charline Peng ,  Patricia Reilly ,  Robert Rothlein ,  Rosemarie H Sellati ,  Joseph R Woska Jr ,  Shirlynn Chen ,  Jocelyn A Gunn ,  Drane O'Brien ,  Stephen H Norris ,  Terence A Kelly
Affiliations
  • 1. Research and Development, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Road, Ridgefield, Connecticut 06877, USA. [email protected]
PMID: 15481974 DOI: 10.1021/jm049657b
Abstract

A novel class of lymphocyte function-associated antigen-1 (LFA-1) inhibitors is described. Discovered during the process to improve the physicochemical and metabolic properties of BIRT377 (1, Figure 1), a previously reported hydantoin-based LFA-1 inhibitor, these compounds are characterized by an imidazole-based 5,5-bicyclic scaffold, the 1,3,3-trisubstituted 1H-imidazo[1,2-alpha]imidazol-2-one (i.e. structure 3). The structure-activity relationship (SAR) shows that electron-withdrawing groups at C5 on the imidazole ring benefit potency and that oxygen-containing functional groups attached to a C5-sulfonyl or sulfonamide group further improve potency. This latter gain in potency is attributed to the interaction(s) of the functionalized sulfonyl/sulfonamide groups with the protein, likely polar-polar in nature, as suggested by SAR data. X-ray studies revealed that these bicyclic inhibitors bind to the I-domain of LFA-1 in a pattern similar to that of compound 1.