Design and synthesis of a new class of selective integrin alpha5beta1 antagonists.
Starting from the structure of integrin alphavbeta3 in a complex with a peptidic ligand plus SAR data on nonpeptidic ligands, we derived a new class of integrin alpha5beta1 antagonists (1). Several synthesis strategies were applied to evaluate the chemical space around the essential pharmacophore groups R1 to R3 to obtain highly active and selective pyrrolidine derivatives as integrin alpha5beta1 antagonists. Integrin selectivity was controlled by switching from a sulfonamide moiety to a mesitylene amide moiety for R3. This finding represents a general feature for modulating selectivity toward other related integrin receptors. On the basis of the encouraging results from various in vitro studies, the most active compounds were selected for further in vivo studies in animal models and preclinical development.
Stragies
Roland
R
Jerini AG, Invalidenstrasse 130, D-10115 Berlin, Germany. stragies@jerini.com
Osterkamp
Frank
F
Zischinsky
Gunther
G
Vossmeyer
Doerte
D
Kalkhof
Holger
H
Reimer
Ulf
U
Zahn
Grit
G
D015195:Drug Design; D004952:Esters; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D039302:Integrin alphaVbeta3 / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000737:chemistry; D011487:Protein Conformation; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry
D004952:Esters; D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3; D008024:Ligands; D010456:Peptides, Cyclic; D011725:Pyridines; D011759:Pyrrolidines; D013449:Sulfonamides