Novel, potent non-covalent thrombin inhibitors incorporating p(3)-lactam scaffolds.
Evolution of P(1)-argininal inhibitor prototypes led to a series of non-covalent P(3)-7-membered lactam inhibitors 1a-w, featuring novel peptidomimetic units that probe each of the S(1), S(2), and S(3) specificity pockets of thrombin. Rigid P(1)-arginine surrogates possessing a wide range of basicity (calcd pK(a)'s approximately neutral-14) were surveyed. The design, synthesis, and biological activity of these targets are presented.
Ho
Jonathan Z
JZ
Department of Medicinal Chemistry, Corvas International, Inc., 3030 Science Park Road, 92121, San Diego, CA, USA
Gibson
Tony S
TS
Semple
J Edward
JE
D000818:Animals; D000991:Antithrombins / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001777:Blood Coagulation / Q000187:drug effects; D004285:Dogs; D007769:Lactams / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015394:Molecular Structure; D012697:Serine Endopeptidases / Q000378:metabolism; D013329:Structure-Activity Relationship; D014357:Trypsin / Q000494:pharmacology
D000991:Antithrombins; D007769:Lactams; D012697:Serine Endopeptidases; D014357:Trypsin