RESUMEN
In recent decades, artificial intelligence and machine learning have played a significant role in increasing the efficiency of processes across a wide spectrum of industries. When it comes to the pharmaceutical and biotechnology sectors, numerous tools enabled by advancement of computer science have been developed and are now routinely utilized. However, there are many aspects of the drug discovery process, which can further benefit from refinement of computational methods and tools, as well as improvement of accessibility of these new technologies. In this review, examples of recent developments in machine learning application are described, which have the potential to impact different parts of the drug discovery and development flow scheme. Notably, new deep learning-based approaches across compound design and synthesis, prediction of binding, activity and ADMET properties, as well as applications of genetic algorithms are highlighted.
Asunto(s)
Aprendizaje Automático , Animales , Química Farmacéutica , Humanos , Modelos Moleculares , Relación Estructura-Actividad CuantitativaRESUMEN
Sodium-phosphate cotransporter 2a, or NaPi2a (SLC34A1), is a solute-carrier (SLC) transporter located in the kidney proximal tubule that reabsorbs glomerular-filtered phosphate. Inhibition of NaPi2a may enhance urinary phosphate excretion and correct maladaptive mineral and hormonal derangements associated with increased cardiovascular risk in chronic kidney disease-mineral and bone disorder (CKD-MBD). To date, only nonselective NaPi inhibitors have been described. Herein, we detail the discovery of the first series of selective NaPi2a inhibitors, resulting from optimization of a high-throughput screening hit. The oral PK profile of inhibitor PF-06869206 (6f) in rodents allows for the exploration of the pharmacology of selective NaPi2a inhibition.
RESUMEN
Optimization of the pharmacokinetic (PK) properties of a series of activators of adenosine monophosphate-activated protein kinase (AMPK) is described. Derivatives of the previously described 5-aryl-indole-3-carboxylic acid clinical candidate (1) were examined with the goal of reducing glucuronidation rate and minimizing renal excretion. Compounds 10 (PF-06679142) and 14 (PF-06685249) exhibited robust activation of AMPK in rat kidneys as well as desirable oral absorption, low plasma clearance, and negligible renal clearance in preclinical species. A correlation of in vivo renal clearance in rats with in vitro uptake by human and rat renal organic anion transporters (human OAT/rat Oat) was identified. Variation of polar functional groups was critical to mitigate active renal clearance mediated by the Oat3 transporter. Modification of either the 6-chloroindole core to a 4,6-difluoroindole or the 5-phenyl substituent to a substituted 5-(3-pyridyl) group provided improved metabolic stability while minimizing propensity for active transport by OAT3.
Asunto(s)
Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Activadores de Enzimas/síntesis química , Activadores de Enzimas/farmacología , Indoles/síntesis química , Indoles/farmacología , Animales , Activación Enzimática/efectos de los fármacos , Activadores de Enzimas/farmacocinética , Humanos , Indoles/farmacocinética , Absorción Intestinal , Riñón/efectos de los fármacos , Riñón/enzimología , Masculino , Modelos Moleculares , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
A domino Rh- and Pd-catalyzed synthesis of dihydroquinolines is disclosed. Two metals and two ligands are placed in one reaction vessel along with the two reactive reagents to afford selective sequential coupling despite the potential for side reactions. In this report, we describe mechanistic investigations attempting to discern the catalyst-ligand interactions occurring in this domino reaction. Through these studies, the reactivity and relative catalyst ligand loadings were successfully tuned to efficiently access the heterocyclic products.
Asunto(s)
Complejos de Coordinación/química , Hidroquinonas/síntesis química , Paladio/química , Rodio/química , Catálisis , Hidroquinonas/química , Ligandos , Estructura MolecularRESUMEN
A Rh(I)/Pd(0) catalyst system was applied to the multicomponent synthesis of aza-dibenzazepines from vinylpyridines, arylboronic acids, and amines in a domino process with no intermediate isolation or purification.
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Aminas/química , Ácidos Borónicos/química , Dibenzazepinas/síntesis química , Paladio/química , Piridinas/química , Rodio/química , Catálisis , Dibenzazepinas/química , Estructura MolecularRESUMEN
A convenient approach toward polycyclic frameworks containing fused 1,2,3-triazoles is described. The synthesis consists of a Cu-catalyzed cycloaddition and an intramolecular Pd-catalyzed direct arylation or Heck reaction, and affords the products in good to excellent yields.
Asunto(s)
Técnicas de Química Sintética/métodos , Halogenación , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/síntesis química , Paladio/química , Triazoles/química , Catálisis , CiclizaciónRESUMEN
A regio- and stereoselective rhodium-catalyzed synthesis of trisubstituted allylic alcohols is described. The utility of these synthons is demonstrated in a convenient synthesis of indenes and quinolines.
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Alquinos/química , Ácidos Borónicos/química , Indenos/síntesis química , Propanoles/química , Quinolinas/síntesis química , Alquilación , Catálisis , Ciclización , Estructura Molecular , Rodio/química , EstereoisomerismoRESUMEN
Although the chemistry of arynes is well developed, some challenges still remain. The ene reaction of arynes has not gained widespread use in synthesis as a result of poor yields and selectivity. A general, high yielding and selective intramolecular aryne-ene reaction is described providing various benzofused carbo- and heterocycles. Mechanistic data is presented, and a rationale for the resulting stereochemistry is discussed.
Asunto(s)
Compuestos Orgánicos/síntesis química , Compuestos Orgánicos/químicaRESUMEN
A highly modular approach to fused 1,2,3-triazoles has been developed featuring a one-pot procedure combining copper(I) catalyzed azide-alkyne cycloaddition and palladium-catalyzed C-H bond functionalization. A class of structurally unique heterocycles was synthesized in good yields.