title: Crystallographic, spectroscopic, and theoretical investigation of the efficiently separated 21R and 21S-diastereoisomers of argatroban.
abstract: Argatroban (I), a potent noncovalent reversible thrombin inhibitor, is used as an anticoagulant for the parenteral treatment of heparin-induced thrombocytopenia (HIT) patients. By virtue of its pharmacological properties and the well-balanced risks and benefits, argatroban is now emerging as a clinically relevant antithrombotic agent. The availability of this drug as a mixture of 21R and 21S-diastereoisomers, in a ratio of roughly 64:36, prompted us to design an efficient separation setup of the two epimers. We pursued our efforts on their detailed structural analysis with the aim of understanding their different activity and aqueous solubility. These investigations were accompanied by a modeling study of the two diastereoisomers, with particular attention on the easy interconverting half-chair of the tetrahydroquinoline system and its preferred conformation, which is determined by the configuration at C21. These results, together with the analysis of their physicochemical profiles, provide new useful information for the development of the individual diastereoisomers.
authors: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano, Italy.
authors: Patrizia
authors: P
authors: Ferraboschi
authors: Diego
authors: D
authors: Colombo
authors: Laura
authors: L
authors: Legnani
authors: Lucio
authors: L
authors: Toma
authors: Paride
authors: P
authors: Grisenti
authors: Giulio
authors: G
authors: Vistoli
authors: Fiorella
authors: F
authors: Meneghetti
mesh_terms: D001120:Arginine / Q000031:analogs & derivatives; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010875:Pipecolic Acids / Q000737:chemistry*; D013237:Stereoisomerism; D013449:Sulfonamides; D013816:Thermodynamics
chemical_list: D010875:Pipecolic Acids; D013449:Sulfonamides; D001120:Arginine; C031942:argatroban
keywords: argatroban; computational chemistry; direct thrombin inhibitors; solubility; structure-activity relationships