RESUMEN
Screening of a fragment library for PDE10A inhibitors identified a low molecular weight pyrimidine hit with PDE10A Ki of 8700 nM and LE of 0.59. Initial optimization by catalog followed by iterative parallel synthesis guided by X-ray cocrystal structures resulted in rapid potency improvements with minimal loss of ligand efficiency. Compound 15 h, with PDE10A Ki of 8.2 pM, LE of 0.49, and >5000-fold selectivity over other PDEs, fully attenuates MK-801-induced hyperlocomotor activity after ip dosing.
Asunto(s)
Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Relación Estructura-Actividad , Animales , Técnicas de Química Sintética , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos/métodos , Humanos , Masculino , Inhibidores de Fosfodiesterasa/síntesis química , Hidrolasas Diéster Fosfóricas/química , Hidrolasas Diéster Fosfóricas/metabolismo , Pirimidinas/química , Ratas Wistar , Esquizofrenia/tratamiento farmacológicoRESUMEN
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be a key component of highly active antiretroviral therapy (HAART). The use of NNRTIs has become part of standard combination antiviral therapies producing clinical outcomes with efficacy comparable to other antiviral regimens. There is, however, a critical issue with the emergence of clinical resistance, and a need has arisen for novel NNRTIs with a broad spectrum of activity against key HIV-1 RT mutations. Using a combination of traditional medicinal chemistry/SAR analyses, crystallography, and molecular modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Further refinement of key compounds in this series to optimize physical properties and pharmacokinetics has resulted in the identification of 8e (MK-4965), which has high levels of potency against wild-type and key mutant viruses, excellent oral bioavailability and overall pharmacokinetics, and a clean ancillary profile.
Asunto(s)
Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , VIH-1/enzimología , Pirazoles/síntesis química , Pirazoles/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Administración Oral , Animales , Compuestos de Bromina/síntesis química , Compuestos de Bromina/química , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Transcriptasa Inversa del VIH/química , Transcriptasa Inversa del VIH/genética , Transcriptasa Inversa del VIH/metabolismo , VIH-1/genética , Modelos Moleculares , Estructura Molecular , Mutación/genética , Nucleósidos/química , Nucleósidos/farmacología , Pirazoles/química , Piridinas/química , Ratas , Ratas Sprague-Dawley , Inhibidores de la Transcriptasa Inversa/química , Relación Estructura-ActividadRESUMEN
From HTS lead 1, a novel benzoisoquinolinone class of ATP-competitive Chk1 inhibitors was devised and synthesized via a photochemical route. Using X-ray crystallography as a guide, potency was rapidly enhanced through the installation of a tethered basic amine designed to interact with an acidic residue (Glu91) in the enzyme pocket. Further SAR was explored at the solvent front and near to the H1 pocket and resulted in the discovery of low MW, sub-nanomolar inhibitors of Chk1.