Solution-phase and solid-phase synthesis of novel transition state inhibitors of coagulation enzymes incorporating a piperidinyl moiety.
2-Amino-3-piperidin-4-yl-propionic acid containing peptidomimetics are potent protease inhibitors when combined with an appropriate keto-thiazole or keto-carboxylic acid moiety. A novel P1 residue in factor Xa and thrombin inhibitors has been found resulting in IC50 values as low as 0.048 microM, a factor of ten more potent than Argatroban. Starting with non-chiral synthetic routes, a new stereospecific route was developed as well as a new solid-phase method.
Adang
A E
AE
Lead Discovery Unit, Research and Development, NV Organon, Oss, The Netherlands.
Peters
A M
AM
Gerritsma
S
S
de Zwart
E
E
Veeneman
G
G
D001779:Blood Coagulation Factors / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis*; D002264:Carboxylic Acids / Q000737:chemistry; D065427:Factor Xa Inhibitors; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008956:Models, Chemical; D010880:Piperidines / Q000737:chemistry*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D013844:Thiazoles / Q000737:chemistry; D013917:Thrombin / Q000037:antagonists & inhibitors
D001779:Blood Coagulation Factors; D002264:Carboxylic Acids; D065427:Factor Xa Inhibitors; D010880:Piperidines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013844:Thiazoles; C032727:piperidine; D013917:Thrombin