title: 3-amino-4-sulfonylpyridinone acetamide and related pyridothiadiazine thrombin inhibitors.
abstract: We describe a series of highly potent and efficacious thrombin inhibitors based on a 3-amino-4-sulfonylpyridinone acetamide template. The functionally dense sulfonyl group stabilizes the aminopyridinone, conformationally constrains the 4-substituent, and forms a hydrogen bond to the insertion loop tyrosine OH. We also describe a related series of fused bicyclic dihydrothiadiazinedioxide derivatives, of which one had improved pharmacokinetics in dogs after oral dosing.
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: Kelly L
authors.initials: KL
authors.lastname: Savage
authors.forename: Adel M
authors.initials: AM
authors.lastname: Naylor-Olsen
authors.forename: Denise J
authors.initials: DJ
authors.lastname: Bickel
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Bohn
authors.forename: Franklin C
authors.initials: FC
authors.lastname: Clayton
authors.forename: Julie A
authors.initials: JA
authors.lastname: Krueger
authors.forename: S Dale
authors.initials: SD
authors.lastname: Lewis
authors.forename: Bobby J
authors.initials: BJ
authors.lastname: Lucas
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Lyle
authors.forename: Audrey A
authors.initials: AA
authors.lastname: Wallace
authors.forename: Denice C
authors.initials: DC
authors.lastname: Welsh
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
mesh_terms: D000081:Acetamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D005290:Ferric Compounds / Q000633:toxicity; D006801:Humans; D008958:Models, Molecular; D011728:Pyridones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013829:Thiadiazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000139:chemically induced; D014361:Trypsin Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000081:Acetamides; D005290:Ferric Compounds; D011728:Pyridones; D013450:Sulfones; D013829:Thiadiazines; D014361:Trypsin Inhibitors; D013917:Thrombin