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 pote nt protease inhibitors when combined with an appropriate keto-thiazole or k eto-carboxylic acid moiety. A novel P-1 residue in factor Xa and thrombin i nhibitors has been found resulting in IC50 values as low as 0.048 mu M, a f actor of ten more potent than Argatroban. Starting with non-chiral syntheti c routes, a new stereospecific route was developed as well as a new solid-p hase method. (C) 1999 Elsevier Science Ltd. All rights reserved.