ABSTRACT
The first solid-phase synthesis of zatebradine 1 and its analogues is reported. This has resulted in the preparation of compounds with increased ability to reduce the spontaneous beating of isolated guinea-pig atria in a concentration-dependent manner. One example, 8g, showed a maximum reduction of beating of 80% at 3 microM compared to a reduction of 40% at 3 microM with zatebradine 1.
Subject(s)
Benzazepines/chemistry , Benzazepines/pharmacology , Cardiotonic Agents/chemistry , Cardiotonic Agents/pharmacology , Animals , Atrial Function , Benzazepines/chemical synthesis , Combinatorial Chemistry Techniques , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Guinea Pigs , Heart Atria/drug effects , In Vitro Techniques , Structure-Activity RelationshipABSTRACT
Thrombin inhibitors have been designed with the replacement of the strongly basic guanidine P1 pharmocophore with a group that exploits the lipophilicity of the S1 pocket. The approach has lead to the discovery of potent thrombin inhibitors demonstrating good intra-duodenal absorption.
Subject(s)
Thrombin/administration & dosage , Thrombin/antagonists & inhibitors , Animals , Biological Availability , Humans , Intestinal Absorption , Rats , Rats, Sprague-Dawley , Thrombin/pharmacokineticsABSTRACT
The optimisation of the P2 pharmacophore in a series of thrombin inhibitors is described. The interaction of a number of piperidine P2 functionalities with lysine 60G of thrombin is explored with reference to the crystal structure of inhibitor enzyme complexes. A primary ion-dipole interaction between the terminal P2 side chain group and lysine 60G is evoked to explain the SAR in this series.
