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

A E Adang; A M Peters; S Gerritsma; E de Zwart; G Veeneman

doi:10.1016/s0960-894x(99)00179-1

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

Bioorg Med Chem Lett. 1999 May 3;9(9):1227-32. doi: 10.1016/s0960-894x(99)00179-1.

Authors

A E Adang¹, A M Peters, S Gerritsma, E de Zwart, G Veeneman

Affiliation

¹ Lead Discovery Unit, Research and Development, NV Organon, Oss, The Netherlands.

PMID: 10340604
DOI: 10.1016/s0960-894x(99)00179-1

Abstract

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.

Publication types

Comparative Study

MeSH terms

Blood Coagulation Factors / antagonists & inhibitors*
Blood Coagulation Factors / chemical synthesis*
Carboxylic Acids / chemistry
Factor Xa Inhibitors
Inhibitory Concentration 50
Kinetics
Models, Chemical
Piperidines / chemistry*
Platelet Glycoprotein GPIIb-IIIa Complex / antagonists & inhibitors
Thiazoles / chemistry
Thrombin / antagonists & inhibitors

Substances

Blood Coagulation Factors
Carboxylic Acids
Factor Xa Inhibitors
Piperidines
Platelet Glycoprotein GPIIb-IIIa Complex
Thiazoles
piperidine
Thrombin