From natural products to achiral drug prototypes: potent thrombin inhibitors based on P2/P3 dihydropyrid-2-one core motifs.
A series of dihydropyrid-2-ones was synthesized and tested for inhibitory activity against serine protease enzymes. Moderate to low nanomolar inhibitory activities were obtained against thrombin and excellent selectivity against trypsin was observed.
Hanessian
Stephen
S
Department of Chemistry, Université de Montréal, C. P. 6128, Succ. Centre-Ville, Montréal, P. Q., Canada H3C 3J7. stephen.hanessian@umontreal.ca
Therrien
Eric
E
Zhang
Jianbin
J
Otterlo
Willem van
Wv
Xue
Yafeng
Y
Gustafsson
David
D
Nilsson
Ingemar
I
Fjellström
Ola
O
D000818:Animals; D002417:Cattle; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D014357:Trypsin / Q000378:metabolism
D011728:Pyridones; D015842:Serine Proteinase Inhibitors; D014357:Trypsin; D013917:Thrombin