RESUMO
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.
Assuntos
Aprendizado de Máquina , Animais , Química Farmacêutica , Humanos , Modelos Moleculares , Relação Quantitativa Estrutura-AtividadeRESUMO
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.
RESUMO
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.
Assuntos
Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Ativadores de Enzimas/síntese química , Ativadores de Enzimas/farmacologia , Indóis/síntese química , Indóis/farmacologia , Animais , Ativação Enzimática/efeitos dos fármacos , Ativadores de Enzimas/farmacocinética , Humanos , Indóis/farmacocinética , Absorção Intestinal , Rim/efeitos dos fármacos , Rim/enzimologia , Masculino , Modelos Moleculares , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Complexos de Coordenação/química , Hidroquinonas/síntese química , Paládio/química , Ródio/química , Catálise , Hidroquinonas/química , Ligantes , Estrutura MolecularRESUMO
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.
Assuntos
Aminas/química , Ácidos Borônicos/química , Dibenzazepinas/síntese química , Paládio/química , Piridinas/química , Ródio/química , Catálise , Dibenzazepinas/química , Estrutura MolecularRESUMO
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.
Assuntos
Técnicas de Química Sintética/métodos , Halogenação , Compostos Heterocíclicos/química , Compostos Heterocíclicos/síntese química , Paládio/química , Triazóis/química , Catálise , CiclizaçãoRESUMO
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.
Assuntos
Alcinos/química , Ácidos Borônicos/química , Indenos/síntese química , Propanóis/química , Quinolinas/síntese química , Alquilação , Catálise , Ciclização , Estrutura Molecular , Ródio/química , EstereoisomerismoRESUMO
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.
Assuntos
Compostos Orgânicos/síntese química , Compostos Orgânicos/químicaRESUMO
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.