Current anticoagulant therapy of venous thromboembolism (VTE) is based on parenterally administered heparins and orally administered vitamin K antagonists (e.g., warfarin), but narrow therapeutic window and side effects, such as bleeding, diet and genetic makeup influence, are associated with their use [1]. Recently, key serine proteases of the blood coagulation cascade, such as thrombin (thr) and factor Xa (fXa), have emerged as promising targets for anticoagulants, and indeed several direct inhibitors of thr (e.g., argatroban, dabigatran) and fXa (e.g., rivaroxaban, apixaban) have been introduced in therapy or in advanced clinical trials [2,3]. Some years ago we investigated the isonipecotanilide scaffold for new thr/fXa inhibitors [4]. Further optimization studies led us to develop new benzyloxy derivatives of N-(phenyl)-1-(pyridin-4-yl)piperidine-4-carboxamide, one of them (i.e., the 3-F analog, see below) showing low nanomolar Ki (thr) value, high selectivity against other serine proteases and good anticoagulant activity as measured by the activated partial thromboplastin time (aPTT) test. Physicochemical profiles of the newly synthesized compounds were assessed and their potential oral bioavailability estimated, by measuring effective permeability coefficients using PAMPA (Parallel Artificial Membrane Permeability Assay).
Lead optimization studies, synthesis and biological evaluation of new isonipecotamide-based orally active thrombin inhibitors
DE CANDIA, MODESTO;ALTOMARE, Cosimo Damiano
2011-01-01
Abstract
Current anticoagulant therapy of venous thromboembolism (VTE) is based on parenterally administered heparins and orally administered vitamin K antagonists (e.g., warfarin), but narrow therapeutic window and side effects, such as bleeding, diet and genetic makeup influence, are associated with their use [1]. Recently, key serine proteases of the blood coagulation cascade, such as thrombin (thr) and factor Xa (fXa), have emerged as promising targets for anticoagulants, and indeed several direct inhibitors of thr (e.g., argatroban, dabigatran) and fXa (e.g., rivaroxaban, apixaban) have been introduced in therapy or in advanced clinical trials [2,3]. Some years ago we investigated the isonipecotanilide scaffold for new thr/fXa inhibitors [4]. Further optimization studies led us to develop new benzyloxy derivatives of N-(phenyl)-1-(pyridin-4-yl)piperidine-4-carboxamide, one of them (i.e., the 3-F analog, see below) showing low nanomolar Ki (thr) value, high selectivity against other serine proteases and good anticoagulant activity as measured by the activated partial thromboplastin time (aPTT) test. Physicochemical profiles of the newly synthesized compounds were assessed and their potential oral bioavailability estimated, by measuring effective permeability coefficients using PAMPA (Parallel Artificial Membrane Permeability Assay).I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
