RESUMEN
Glucokinase activators are a class of experimental agents under investigation as a therapy for Type 2 diabetes mellitus. An X-ray crystal structure of a modestly potent agent revealed the potential to substitute the common heterocyclic amide donor-acceptor motif for a pyridone moiety. We have successfully demonstrated that both pyridone and pyrimidone heterocycles can be used as a potent donor-acceptor substituent. Several sub-micromolar analogs that possess the desired partial activator profile were synthesized and characterized. Unfortunately, the most potent activators suffered from sub-optimal pharmacokinetic properties. Nonetheless, these donor-acceptor motifs may find utility in other glucokinase activator series or beyond.
Asunto(s)
Activadores de Enzimas/química , Glucoquinasa/metabolismo , Pirimidinonas/síntesis química , Regulación Alostérica , Secuencias de Aminoácidos , Animales , Sitios de Unión , Modelos Moleculares , Pirimidinonas/química , RatasRESUMEN
The discovery of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor is described. The characterization and redressing of the issues associated with these compounds is detailed. An efficient three-step synthesis and a binding assay were relied upon as the primary means of rapidly improving potency and ADMET properties for this class of inverse agonist compounds. Compound 10 n bearing distributed polarity in the form of an imidazo-thiazole acetamide and a phenyl triazole is a unit lower in logP and has significantly improved binding affinity compared to the hit molecule 10a, providing support for further optimization of this series of compounds.
Asunto(s)
Azetidinas/química , Piperidinas/química , Receptores de Ghrelina/agonistas , Animales , Azetidinas/síntesis química , Azetidinas/farmacocinética , Agonismo Inverso de Drogas , Humanos , Microsomas Hepáticos/metabolismo , Ratas , Receptores de Ghrelina/metabolismo , Relación Estructura-ActividadRESUMEN
Beginning with carbazole 1a, the amide and alkyl substituents were optimized to maintain potency while adding solubilizing groups. Efforts to replace the 3-amino-9-ethylcarbazole core, a known carcinogen, used the SAR generated in the carbazole series for guidance and led to the synthesis of a number of core-modified analogues. In addition, an isosteric series, in which the amide was replaced with an imidazole, was prepared. Two potent new series lacking the putative toxicophore were identified from these endeavors.
Asunto(s)
Amidas/química , Amidas/farmacología , Carbazoles/química , Carbazoles/farmacología , Receptores de Neuropéptido Y/antagonistas & inhibidores , Animales , Calcio/química , Calcio/farmacología , Ingestión de Alimentos/efectos de los fármacos , Humanos , Imidazoles/química , Imidazoles/farmacología , Concentración 50 Inhibidora , Masculino , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Solubilidad , Relación Estructura-ActividadRESUMEN
A series of 2-heteroaryl-4-arylimidazoles with potent in vitro activity at the NPY5 receptor was developed. Introduction of electron-withdrawing groups on the 4-aryl ring led to a significant improvement of in vitro potency. Several analogues from this series had anorectic activity in rodent feeding models, but were also found to have undesired behavioral effects in spontaneous locomotor activity.
Asunto(s)
Imidazoles/química , Imidazoles/farmacología , Receptores de Neuropéptido Y/antagonistas & inhibidores , Animales , Conducta Animal/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Ratas , Relación Estructura-ActividadRESUMEN
In this communication, we wish to describe the discovery of a novel series of 6-azauracil-based thyromimetics that possess up to 100-fold selectivities for binding and functional activation of the beta(1)-isoform of the thyroid receptor family. Structure-activity relationship studies on the 3,5- and 3'-positions provided compounds with enhanced TR beta affinity and selectivity. Key binding interactions between the 6-azauracil moiety and the receptor have been determined through of X-ray crystallographic analysis.