RESUMEN
HIV integrase strand transfer inhibitors (InSTIs) represent an important class of antiviral therapeutics with proven efficacy and excellent tolerability for the treatment of HIV infections. In 2007, Raltegravir became the first marketed strand transfer inhibitor pioneering the way to a first-line therapy for treatment-naïve patients. Challenges with this class of therapeutics remain, including frequency of the dosing regimen and the genetic barrier to resistance. To address these issues, research towards next-generation integrase inhibitors has focused on imparting potency against RAL-resistent mutants and improving pharmacokinetic profiles. Herein, we detail medicinal chemistry efforts on a novel class of 2-pyridinone aminal InSTIs, inpsired by MK-0536, which led to the discovery of important lead molecules for our program. Systematic optimization carried out at the amide and aminal positions on the periphery of the core provided the necessary balance of antiviral activity and physiochemical properties. These efforts led to a novel aminal lead compound with the desired virological profile and preclinical pharmacokinetic profile to support a once-daily human dose prediction.
Asunto(s)
Inhibidores de Integrasa VIH/química , Inhibidores de Integrasa VIH/farmacología , Integrasa de VIH/metabolismo , VIH-1/enzimología , Piridonas/química , Piridonas/farmacología , Animales , Perros , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/farmacocinética , VIH-1/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Piridonas/farmacocinéticaRESUMEN
Biaryl ethers were recently reported as potent NNRTIs. Herein, we disclose a detailed effort to modify the previously reported compound 1. We have designed and synthesized a series of novel pyrazole derivatives as a surrogate for pyrazolopyridine motif that were potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells.
Asunto(s)
Fármacos Anti-VIH/química , Éteres/química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Pirazoles/química , Piridinas/química , Inhibidores de la Transcriptasa Inversa/química , Regulación Alostérica , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacocinética , Perros , Éteres/síntesis química , Éteres/farmacocinética , Transcriptasa Inversa del VIH/genética , Transcriptasa Inversa del VIH/metabolismo , Humanos , Mutación , Pirazoles/síntesis química , Pirazoles/farmacocinética , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacocinética , Relación Estructura-ActividadRESUMEN
Using a combination of traditional Medicinal Chemistry/SAR analysis, crystallography, and molecular modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad antiviral activity against a number of key clinical mutations.
Asunto(s)
Fármacos Anti-VIH/farmacología , Diseño de Fármacos , Éteres/química , VIH-1/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/farmacología , Replicación Viral/efectos de los fármacos , Fármacos Anti-VIH/síntesis química , Sitios de Unión , Cristalografía por Rayos X , Farmacorresistencia Viral , VIH-1/enzimología , VIH-1/genética , Modelos Químicos , Mutación , Nucleósidos/química , Inhibidores de la Transcriptasa Inversa/síntesis química , Relación Estructura-Actividad , Replicación Viral/fisiologíaRESUMEN
The search for new molecular constructs that resemble the critical two-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical pharmacokinetic profiles to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent molecules.
Asunto(s)
Inhibidores de Integrasa VIH/síntesis química , Inhibidores de Integrasa VIH/farmacología , Piridonas/síntesis química , Piridonas/farmacología , Animales , Área Bajo la Curva , Perros , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Integrasa de VIH/efectos de los fármacos , Integrasa de VIH/metabolismo , Inhibidores de Integrasa VIH/farmacocinética , VIH-1/efectos de los fármacos , VIH-1/enzimología , VIH-1/genética , Humanos , Modelos Moleculares , Profármacos , Piridonas/farmacocinética , RatasRESUMEN
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
Pyrimidino-thiazolyl carbonitriles were prepared that are potent VEGFR-2 (KDR) kinase inhibitors. The modification of lead structures resulted in 3m which exhibited the best overall profile in KDR inhibitory activity, iv/po pharmacokinetics, and reduced hERG affinity.
Asunto(s)
Nitrilos/síntesis química , Nitrilos/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Tiazoles/síntesis química , Tiazoles/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Perros , Macaca mulatta , Estructura Molecular , Nitrilos/química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Ratas , Sensibilidad y Especificidad , Relación Estructura-Actividad , Tiazoles/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
We have prepared a series of potent, dual inhibitors of the prenyl transferases farnesyl protein transferase (FPTase) and geranyl-geranyl protein transferase I (GGPTase). The compounds were shown to possess potent activity against both enzymes in cell culture. Mechanistic analysis has shown that the compounds are CAAX competitive for FPTase inhibition but geranyl-geranyl pyrophosphate (GGPP) competitive for GGPTase inhibiton.