Solution-phase and solid-phase synthesis of novel transition state inhibitors of coagulation enzymes incorporating a piperidinyl moiety

• Published in: Bioorganic & medicinal chemistry letters 1999-05, Vol.9 (9), p.1227-1232
• Main Authors: Adang, Anton E.P., Peters, Co A.M., Gerritsma, Siene, de Zwart, Edwin, Veeneman, Gerrit
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Blood Coagulation Factors - antagonists & inhibitors; Blood Coagulation Factors - chemical synthesis; Blood. Blood coagulation. Reticuloendothelial system; Carboxylic Acids - chemistry; Factor Xa Inhibitors; Inhibitory Concentration 50; Kinetics; Medical sciences; Models, Chemical; Pharmacology. Drug treatments; Piperidines - chemistry; Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors; Thiazoles - chemistry; Thrombin - antagonists & inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(99)00179-1

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 P 1 residue in factor Xa and thrombin inhibitors has been found resulting in IC 50 values as low as 0.048 μM, 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. 2-Amino-3-piperidin-4-yl-propionic acid containing peptidomimetics are potent serine protease inhibitors when combined with an appropriate transition state mimic. Starting with non-chiral synthetic routes, a new stereospecific route as well as a new solid-phase method were developed to obtain a spectrum of serine protease inhibitors with piperidine as the P 1 residue. Compound 35b is the most potent and selective example: