RESUMEN
Activated coagulation factor XI (FXIa) is a highly attractive antithrombotic target as it contributes to the development and progression of thrombosis but is thought to play only a minor role in hemostasis so that its inhibition may allow for decoupling of antithrombotic efficacy and bleeding time prolongation. Herein, we report our major efforts to identify an orally bioavailable, reversible FXIa inhibitor. Using a protein structure-based de novo design approach, we identified a novel micromolar hit with attractive physicochemical properties. During lead modification, a critical problem was balancing potency and absorption by focusing on the most important interactions of the lead series with FXIa while simultaneously seeking to improve metabolic stability and the cytochrome P450 interaction profile. In clinical trials, the resulting compound from our extensive research program, asundexian (BAY 2433334), proved to possess the desired DMPK properties for once-daily oral dosing, and even more importantly, the initial pharmacological hypothesis was confirmed.
Asunto(s)
Factor XIa , Fibrinolíticos , AnticoagulantesRESUMEN
The first-in-class soluble guanylate cyclase (sGC) stimulator riociguat was recently introduced as a novel treatment option for pulmonary hypertension. Despite its outstanding pharmacological profile, application of riociguat in other cardiovascular indications is limited by its short half-life, necessitating a three times daily dosing regimen. In our efforts to further optimize the compound class, we have uncovered interesting structure-activity relationships and were able to decrease oxidative metabolism significantly. These studies resulting in the discovery of once daily sGC stimulator vericiguat (compound 24, BAY 1021189), currently in phase 3 trials for chronic heart failure, are now reported.
Asunto(s)
Insuficiencia Cardíaca/tratamiento farmacológico , Compuestos Heterocíclicos con 2 Anillos/química , Compuestos Heterocíclicos con 2 Anillos/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Guanilil Ciclasa Soluble/metabolismo , Relación Estructura-Actividad , Administración Intravenosa , Administración Oral , Animales , Presión Sanguínea/efectos de los fármacos , Técnicas de Química Sintética , Perros , Hepatocitos/efectos de los fármacos , Compuestos Heterocíclicos con 2 Anillos/administración & dosificación , Humanos , Masculino , NG-Nitroarginina Metil Éster/efectos adversos , Pirimidinas/administración & dosificación , Ratas Transgénicas , Ratas Wistar , Guanilil Ciclasa Soluble/genéticaRESUMEN
Cinchona alkaloids catalyze the oxa-Michael cyclization of 4-(2-hydroxyphenyl)-2-butenoates to benzo-2,3-dihydrofuran-2-yl acetates and related substrates in up to 99% yield and 91%â ee (ee = enantiomeric excess). Catalyst and substrate variation studies reveal an important role of the alkaloid hydroxy group in the reaction mechanism, but not in the sense of a hydrogen-bonding activation of the carbonyl group of the substrate as assumed by the Hiemstra-Wynberg mechanism of bifunctional catalysis. Deuterium labeling at C-2 of the substrate shows that addition of RO-H to the alkenoate occurs with syn diastereoselectivity of ≥99:1, suggesting a mechanism-based specificity. A concerted hydrogen-bond network mechanism is proposed, in which the alkaloid hydroxy group acts as a general acid in the protonation of the α-carbanionic center of the product enolate. The importance of concerted hydrogen-bond network mechanisms in organocatalytic reactions is discussed. The relative stereochemistry of protonation is proposed as analytical tool for detecting concerted addition mechanisms, as opposed to ionic 1,4-additions.
RESUMEN
A largely catalysis based approach to optically active haouamine A (-)-1 is presented, which provides the hexacyclic compound previously used to construct this cytotoxic marine alkaloid.
Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Cristalografía por Rayos X , Compuestos Heterocíclicos de 4 o más Anillos/química , Modelos Moleculares , Estructura MolecularRESUMEN
The combination of catalytic amounts of [Pd(PPh3)4], copper thiophene-2-carboxylate (CuTC) and [Ph2PO2][NBu4] allowed a series of exigent Stille-Migita reactions to be performed with high yields; as the protocol is fluoride free, a variety of O-silyl and C-silyl groups remained intact.