3-amino-4-sulfonylpyridinone acetamide and related pyridothiadiazine thrombin inhibitors.
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.
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
Savage
Kelly L
KL
Naylor-Olsen
Adel M
AM
Bickel
Denise J
DJ
Bohn
Dennis L
DL
Clayton
Franklin C
FC
Krueger
Julie A
JA
Lewis
S Dale
SD
Lucas
Bobby J
BJ
Lyle
Elizabeth A
EA
Wallace
Audrey A
AA
Welsh
Denice C
DC
Yan
Youwei
Y
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
D000081:Acetamides; D005290:Ferric Compounds; D011728:Pyridones; D013450:Sulfones; D013829:Thiadiazines; D014361:Trypsin Inhibitors; D013917:Thrombin