Small, low nanomolar, noncovalent thrombin inhibitors lacking a group to fill the 'distal binding pocket'.
Use of a chlorophenoxyacetamide P1 group with a pyridinone acetamide P2/P3 gave an exceptionally potent thrombin inhibitor (K(i)=40 pM). Truncation of the molecule at the N-terminus gave unique, low nanomolar, non-covalent thrombin inhibitors which do not have a group to fill thrombin's 'distal binding pocket'. A co-crystal structure indicates the importance of an intramolecular hydrogen bond between the P1 side chain and P1/P2 amide link in this series.
Sanderson
Philip E J
PE
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. phil_sanderson@merck.com
Cutrona
Kellie J
KJ
Dyer
Dona L
DL
Krueger
Julie A
JA
Kuo
Lawrence C
LC
Lewis
S Dale
SD
Lucas
Bobby J
BJ
Yan
Youwei
Y
D000081:Acetamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D001665:Binding Sites; D003460:Crystallization; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011728:Pyridones / Q000138:chemical synthesis* / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000081:Acetamides; D004791:Enzyme Inhibitors; D011728:Pyridones; D013917:Thrombin