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
Epicolactone is a recently isolated fungal metabolite that is highly complex for its size, and yet racemic. With its array of quaternary stereocentres, high degree of functionalization and intricate polycyclic structure, it poses a considerable challenge to synthesis, a challenge that can be met by understanding its biosynthetic origin. If drawn in a certain way, epicolactone reveals a pattern that resembles purpurogallin, the archetype of ubiquitous natural colourants formed via oxidative dimerization. Based on this insight, we designed a biomimetic synthesis of epicolactone that proceeds in only eight steps from vanillyl alcohol. We have isolated a key intermediate that supports our biosynthetic hypothesis and anticipate that an isomer of epicolactone stemming from our synthetic efforts could also be found as a natural product.
Asunto(s)
Lactonas/síntesis química , Reacción de Cicloadición , Lactonas/químicaRESUMEN
Dibefurin is a Ci -symmetric natural product that acts as an inhibitor of calcineurin phosphatase. A six-step synthesis of this compound is reported, which features an oxidative dimerization of the aromatic polyketide epicoccine as the key step. Dibefurin is proposed to be related to epicolactone, a complex yet racemic fungal metabolite that has recently been discovered. Attempts to access epicolactone from epicoccine and epicocconeâ B resulted in an unusual dimer that is formed through a hetero-Diels-Alder reaction of a para-quinone methide with an ortho-quinone.
Asunto(s)
Benzofuranos/síntesis química , Inhibidores Enzimáticos/síntesis química , Monoéster Fosfórico Hidrolasas/antagonistas & inhibidores , Benzofuranos/química , Biomimética , Reacción de Cicloadición , Dimerización , Inhibidores Enzimáticos/química , Hongos/química , Modelos MolecularesRESUMEN
The development of a highly stereospecific process for the C-O to C-N exchange with retention of configuration is described. This transformation enables access to optically enriched ß-amido-α-diazoesters. These products are transformed to ß-amino acids not readily accessible using known methods.
Asunto(s)
Aminoácidos/síntesis química , Compuestos Azo/química , Aminoácidos/química , Catálisis , Ésteres , Iminas/química , Estructura Molecular , EstereoisomerismoRESUMEN
A novel synthetic strategy toward the asymmetric synthesis of vicinal diols bearing a tertiary center is presented. The method encompasses the dinuclear Mg-catalyzed asymmetric addition of ethyl diazoacetate into several aldehydes, oxidation of the diazo functionality, and diastereoselective alkyl transfer of various organometallics into the resulting chiral ß-hydroxy-α-ketoesters to afford a diverse range of 1,2-diols in high yield, diastereoselectivity, and chirality transfer.