RESUMEN
A series of 4, 4-disubstituted proline analogs were designed, synthesized, and tested for selective inhibition of blood coagulation factor XIa in search of new non-vitamin K antagonists based oral anticoagulants for potential prevention and treatment of thrombotic diseases. Starting from a potent thrombin (FIIa) inhibitor chemotype with FIIa IC50 = 1 nM and FXIa IC50 = 160 nM, medicinal chemistry iterations guided by molecular modeling and structure-based drug design led to steady improvement of FXIa potency while dialing down thrombin activity and improving selectivity. Through this exercise, a thousand-fold enhancement of selectivity over thrombin was achieved with some analogs carrying factor XIa inhibition potencies in the 10 nM range. In this communication, we discuss the design principles and structure activity relationship (SAR) of these novel FXIa selective inhibitors.
Asunto(s)
Anticoagulantes/farmacología , Diseño de Fármacos , Factor XIa/antagonistas & inhibidores , Prolina/farmacología , Anticoagulantes/síntesis química , Anticoagulantes/química , Relación Dosis-Respuesta a Droga , Factor XIa/metabolismo , Humanos , Estructura Molecular , Prolina/síntesis química , Prolina/química , Relación Estructura-ActividadRESUMEN
A series benzylpiperidinium and benzylpyridinium quaternary salts have been synthesised and tested for inhibition of acetylcholinesterase and reversal of neuromuscular block induced by vecuronium. Several potent reversal agents have been identified and their haemodynamic effects measured.
Asunto(s)
Acetilcolinesterasa/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Indanos/farmacología , Fármacos Neuromusculares no Despolarizantes/antagonistas & inhibidores , Piperidinas/farmacología , Bromuro de Vecuronio/antagonistas & inhibidores , Inhibidores de la Colinesterasa/química , Donepezilo , Indanos/química , Piperidinas/químicaRESUMEN
A series of piperidinium and pyridinium agents containing a common structural fragment of 5,6-dimethoxybenzothiophene have been synthesised as water-soluble acetylcholinesterase inhibitors. Several compounds, for example 42 (AChE IC(50) 0.03 microM) have been found to reverse the neuromuscular blockade induced by vecuronium bromide in vitro and in vivo. Coupled with their high water solubility (up to 30-60 mg/mL), these compounds are potentially useful as intravenous reversal agents of neuromuscular blocking agents in surgical anaesthesia.
Asunto(s)
Acetilcolinesterasa/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Fármacos Neuromusculares no Despolarizantes/farmacología , Piperidinas/farmacología , Piridinas/farmacología , Bromuro de Vecuronio/antagonistas & inhibidores , Animales , Inhibidores de la Colinesterasa/química , Cricetinae , Diafragma/efectos de los fármacos , Fármacos Neuromusculares no Despolarizantes/química , Piperidinas/química , Piridinas/química , Solubilidad , AguaRESUMEN
A series of oxyanilinium-based AChE inhibitors have been synthesised and tested for the reversal of vecuronium-induced neuromuscular block. Several compounds, for example 2-hydroxy- and 2-methoxy-N,N-dimethyl-N-allylanilinium bromide (3 and 6) showed comparable reversal potencies to edrophonium and clean in vivo cardiovascular profiles.