Design, synthesis, and thrombin-inhibitory activity of pyridin-2-ones as P2/P3 core motifs.
Guided by available X-ray crystal structure data on the serine protease thrombin, a series of pyridin-2-one derivatives were designed and synthesized having diverse functionality at the P(1) and P(3) sites. Potent in vitro activity against thrombin, with excellent selectivity over trypsin was found for selected analogues.
Hanessian
Stephen
S
Department of Chemistry, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, Que., Canada H3C 3J7. stephen.hanessian@umontreal.ca
Simard
Daniel
D
Bayrakdarian
Malken
M
Therrien
Eric
E
Nilsson
Ingemar
I
Fjellström
Ola
O
D000588:Amines / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014357:Trypsin / Q000737:chemistry / Q000378:metabolism
D000588:Amines; D011728:Pyridones; D013449:Sulfonamides; C017679:2-hydroxypyridine; D014357:Trypsin; D013917:Thrombin