title: Small, low nanomolar, noncovalent thrombin inhibitors lacking a group to fill the 'distal binding pocket'.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. phil_sanderson@merck.com
authors.forename: Philip E J
authors.initials: PE
authors.lastname: Sanderson
authors.forename: Kellie J
authors.initials: KJ
authors.lastname: Cutrona
authors.forename: Dona L
authors.initials: DL
authors.lastname: Dyer
authors.forename: Julie A
authors.initials: JA
authors.lastname: Krueger
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Kuo
authors.forename: S Dale
authors.initials: SD
authors.lastname: Lewis
authors.forename: Bobby J
authors.initials: BJ
authors.lastname: Lucas
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
mesh_terms: 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
chemical_list: D000081:Acetamides; D004791:Enzyme Inhibitors; D011728:Pyridones; D013917:Thrombin