Second-generation lymphocyte function-associated antigen-1 inhibitors: 1H-imidazo[1,2-alpha]imidazol-2-one derivatives.
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.
Wu
Jiang-Ping
JP
Research and Development, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Road, Ridgefield, Connecticut 06877, USA. jwu@rdg.boehringer-ingelheim.com
Emeigh
Jonathan
J
Gao
Donghong A
DA
Goldberg
Daniel R
DR
Kuzmich
Daniel
D
Miao
Clara
C
Potocki
Ian
I
Qian
Kevin C
KC
Sorcek
Ronald J
RJ
Jeanfavre
Deborah D
DD
Kishimoto
Kei
K
Mainolfi
Elizabeth A
EA
Nabozny
Gerald
G
Peng
Charline
C
Reilly
Patricia
P
Rothlein
Robert
R
Sellati
Rosemarie H
RH
Woska
Joseph R
JR
Chen
Shirlynn
S
Gunn
Jocelyn A
JA
O'Brien
Drane
D
Norris
Stephen H
SH
Kelly
Terence A
TA
D018360:Crystallography, X-Ray; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry*; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D007093:Imidazoles; D016169:Lymphocyte Function-Associated Antigen-1