RESUMEN
This manuscript describes the development of the first diastereoselective intermolecular synthesis of alkyl ethers via reductive etherification of diverse ketones or aldehydes with alcohols. Key to this development was the use of low-temperature high-throughput experimentation (HTE) technologies that enabled rapid reaction optimizations and parallel synthesis. A broad scope of pharmaceutically relevant substrates was surveyed, which formed alkyl ethers effectively. In addition, we demonstrated that the diastereoselectivity of this transformation can be readily modulated by prudent selection of the reductant.
RESUMEN
Using structure based drug design (SBDD), a novel class of potent coagulation Factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds demonstrated oral bioavailability in rat IV/PO pharmacokinetic (PK) studies. Finally, the pharmacodynamics (PD) of this class of molecules was evaluated in Thrombin Generation Assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.
Asunto(s)
Aminas/farmacología , Inhibidores Enzimáticos/farmacología , Factor IXa/antagonistas & inhibidores , Administración Oral , Aminas/síntesis química , Aminas/química , Animales , Disponibilidad Biológica , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Factor IXa/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
The cyclopropanation of alkenyl boronates and subsequent derivatization of the boronate handle are a convenient strategy to quickly build molecular complexity and access diverse compounds with a high sp3 fraction. Herein, we describe the asymmetric cyclopropanation of enantioenriched hydrobenzoin-derived alkenyl boronic esters toward the synthesis of tertiary and secondary cyclopropyl boronates.
Asunto(s)
Boro , Ésteres , Ácidos Borónicos , EstereoisomerismoRESUMEN
Inhibitor cystine knot peptides, derived from venom, have evolved to block ion channel function but are often toxic when dosed at pharmacologically relevant levels in vivo. The article describes the design of analogues of ProTx-II that safely display systemic in vivo blocking of Nav1.7, resulting in a latency of response to thermal stimuli in rodents. The new designs achieve a better in vivo profile by improving ion channel selectivity and limiting the ability of the peptides to cause mast cell degranulation. The design rationale, structural modeling, in vitro profiles, and rat tail flick outcomes are disclosed and discussed.
Asunto(s)
Canal de Sodio Activado por Voltaje NAV1.7/efectos de los fármacos , Dolor/tratamiento farmacológico , Bloqueadores de los Canales de Sodio/síntesis química , Bloqueadores de los Canales de Sodio/farmacología , Venenos de Araña/síntesis química , Animales , Degranulación de la Célula/efectos de los fármacos , Cistina/química , Diseño de Fármacos , Calor , Mastocitos/efectos de los fármacos , Modelos Moleculares , Dimensión del Dolor/efectos de los fármacos , Ratas , Venenos de Araña/farmacologíaRESUMEN
A series of biaryl chromans exhibiting potent and selective agonism for the GPR40 receptor with positive allosteric modulation of endogenous ligands (AgoPAM) were discovered as potential therapeutics for the treatment of type II diabetes. Optimization of physicochemical properties through modification of the pendant aryl rings resulted in the identification of compound AP5, which possesses an improved metabolic profile while demonstrating sustained glucose lowering.
RESUMEN
GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia. GPR40 agoPAMs have shown superior efficacy to partial agonists as assessed in a glucose tolerability test (GTT). Herein, we report the discovery and optimization of a series of potent, selective GPR40 agoPAMs. Compound 24 demonstrated sustained glucose lowering in a chronic study of Goto Kakizaki rats, showing no signs of tachyphylaxis for this mechanism.
RESUMEN
The development of a convergent and highly stereoselective synthesis of an HCV NS3/4a protease inhibitor possessing a unique spirocyclic and macrocyclic architecture is described. A late-stage spirocyclization strategy both enabled rapid structure-activity relationship studies in the drug discovery phase and simultaneously served as the basis for the large scale drug candidate preparation for clinical use. Also reported is the discovery of a novel InCl3-catalyzed carbonyl reduction with household aluminum foil or zinc powder as the terminal reductant.