RESUMEN
Herein we describe the discovery of a novel series of pyrrolo[1,2-a]pyrazin-1(2H)-one PARP inhibitors. Optimization led to compounds that display excellent PARP-1 enzyme potency and inhibit the proliferation of BRCA deficient cells in the low double-digit nanomolar range showing excellent selectivity over BRCA proficient cancer cells.
Asunto(s)
Inhibidores de Poli(ADP-Ribosa) Polimerasas , Pirazinas/química , Pirazinas/metabolismo , Animales , Proteína BRCA1/deficiencia , Proteína BRCA1/metabolismo , Línea Celular Tumoral , Cristalografía por Rayos X , Células HeLa , Humanos , Indolizinas/química , Indolizinas/metabolismo , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/metabolismo , Unión Proteica/fisiología , Ratas , Relación Estructura-ActividadRESUMEN
In the context of HIV-integrase, dihydroxypyrimidine and N-methyl pyrimidone inhibitors the cellular activity of this class of compounds has been optimized by the introduction of a simple methyl substituent in the alpha-position of the C-2 side chains. Enhanced passive membrane permeability has been identified as the key factor driving the observed cell-based activity improvement. The rat PK profile of the alpha-methyl derivative 26a was also improved over its des-methyl exact analog.
Asunto(s)
Inhibidores de Integrasa VIH/química , Integrasa de VIH/química , Pirimidinas/química , Pirimidinonas/química , Animales , Permeabilidad de la Membrana Celular , Integrasa de VIH/metabolismo , Inhibidores de Integrasa VIH/síntesis química , Inhibidores de Integrasa VIH/farmacocinética , Humanos , Unión Proteica , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Pirimidinonas/síntesis química , Pirimidinonas/farmacocinética , RatasRESUMEN
The optimization of a potent, class I selective ketone HDAC inhibitor is shown. It possesses optimized pharmacokinetic properties in preclinical species, has a clean off-target profile, and is negative in a microbial mutagenicity (Ames) test. In a mouse xenograft model it shows efficacy comparable to that of vorinostat at a 10-fold reduced dose.
Asunto(s)
Antineoplásicos/farmacocinética , Inhibidores Enzimáticos/farmacocinética , Inhibidores de Histona Desacetilasas , Quinolinas/farmacocinética , Animales , Antineoplásicos/síntesis química , Línea Celular Tumoral , Perros , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Células HeLa , Humanos , Ratones , Quinolinas/síntesis química , RatasRESUMEN
Human immunodeficiency virus type-1 (HIV-1) integrase is one of the three virally encoded enzymes required for replication and therefore a rational target for chemotherapeutic intervention in the treatment of HIV-1 infection. We report here the discovery of Raltegravir, the first HIV-integrase inhibitor approved by FDA for the treatment of HIV infection. It derives from the evolution of 5,6-dihydroxypyrimidine-4-carboxamides and N-methyl-4-hydroxypyrimidinone-carboxamides, which exhibited potent inhibition of the HIV-integrase catalyzed strand transfer process. Structural modifications on these molecules were made in order to maximize potency as HIV-integrase inhibitors against the wild type virus, a selection of mutants, and optimize the selectivity, pharmacokinetic, and metabolic profiles in preclinical species. The good profile of Raltegravir has enabled its progression toward the end of phase III clinical trials for the treatment of HIV-1 infection and culminated with the FDA approval as the first HIV-integrase inhibitor for the treatment of HIV-1 infection.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/farmacología , Pirrolidinonas/farmacología , Administración Oral , Área Bajo la Curva , Disponibilidad Biológica , Inhibidores de Integrasa VIH/administración & dosificación , Inhibidores de Integrasa VIH/farmacocinética , Inhibidores de Integrasa VIH/uso terapéutico , Semivida , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Pirrolidinonas/administración & dosificación , Pirrolidinonas/farmacocinética , Pirrolidinonas/uso terapéutico , Raltegravir PotásicoRESUMEN
Histone deacetylase (HDAC) inhibitors offer a promising strategy for cancer therapy and the first generation HDAC inhibitors are currently in the clinic. Herein we describe the optimization of a series of ketone small molecule HDAC inhibitors leading to potent and selective class I HDAC inhibitors with good dog PK.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores de Histona Desacetilasas , Histona Desacetilasas/metabolismo , Cetonas/química , Administración Oral , Animales , Proliferación Celular , Perros , Inhibidores Enzimáticos/farmacología , Células HeLa , Histona Desacetilasa 1 , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Ratas , Proteínas Recombinantes/química , Zinc/químicaRESUMEN
Histone deacetylase (HDAC) inhibitors offer a promising strategy for cancer therapy, and the first generation HDAC inhibitors are currently in the clinic. Entirely novel ketone HDAC inhibitors have been developed from the cyclic tetrapeptide apicidin. These compounds show class I subtype selectivity and levels of cellular activity comparable to clinical candidates. A representative example has demonstrated tumor growth inhibition in a human colon HCT-116 carcinoma xenograft model comparable to known inhibitors.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Cetonas/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Histona Desacetilasas/química , Humanos , Estructura MolecularRESUMEN
HIV integrase is one of the three enzymes encoded by HIV genome and is essential for viral replication, but integrase inhibitors as marketed drugs have just very recently started to emerge. In this study, we show the evolution from the N-methylpyrimidinone structure to bicyclic pyrimidinones. Introduction of a suitably substituted amino moiety modulated the physical-chemical properties of the molecules and conferred nanomolar activity in the inhibition of spread of HIV-1 infection in cell culture. An extensive SAR study led to sulfamide (R)- 22b, which inhibited the strand transfer with an IC50 of 7 nM and HIV infection in MT4 cells with a CIC95 of 44 nM, and ketoamide (S)- 28c that inhibited strand transfer with an IC50 of 12 nM and the HIV infection in MT4 cells with a CIC95 of 13 nM and exhibited a good pharmacokinetic profile when dosed orally to preclinical species.
Asunto(s)
Aminopiridinas/síntesis química , Azepinas/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Inhibidores de Integrasa VIH/síntesis química , Integrasa de VIH/metabolismo , Pirimidinonas/síntesis química , Administración Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacología , Animales , Azepinas/farmacocinética , Azepinas/farmacología , Disponibilidad Biológica , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular , Perros , Integrasa de VIH/genética , Inhibidores de Integrasa VIH/farmacocinética , Inhibidores de Integrasa VIH/farmacología , VIH-1/efectos de los fármacos , Humanos , Macaca mulatta , Microsomas Hepáticos/metabolismo , Pirimidinonas/farmacocinética , Pirimidinonas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The human immunodeficiency virus type-1 (HIV-1) encodes three enzymes essential for viral replication: a reverse transcriptase, a protease, and an integrase. The latter is responsible for the integration of the viral genome into the human genome and, therefore, represents an attractive target for chemotherapeutic intervention against AIDS. A drug based on this mechanism has not yet been approved. Benzyl-dihydroxypyrimidine-carboxamides were discovered in our laboratories as a novel and metabolically stable class of agents that exhibits potent inhibition of the HIV integrase strand transfer step. Further efforts led to very potent compounds based on the structurally related N-Me pyrimidone scaffold. One of the more interesting compounds in this series is the 2-N-Me-morpholino derivative 27a, which shows a CIC95 of 65 nM in the cell in the presence of serum. The compound has favorable pharmacokinetic properties in three preclinical species and shows no liabilities in several counterscreening assays.
Asunto(s)
Inhibidores de Integrasa VIH/síntesis química , Integrasa de VIH/química , VIH-1/efectos de los fármacos , Morfolinas/síntesis química , Pirimidinonas/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Proteínas Sanguíneas/metabolismo , Línea Celular Tumoral , Perros , Inhibidores de Integrasa VIH/farmacocinética , Inhibidores de Integrasa VIH/farmacología , VIH-1/enzimología , VIH-1/fisiología , Humanos , Macaca mulatta , Morfolinas/farmacocinética , Morfolinas/farmacología , Unión Proteica , Pirimidinonas/farmacocinética , Pirimidinonas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
A series of aryltetrazolylacetanilides was synthesized and evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors on wild-type virus and on the clinically relevant K103N mutant strain. Extensive SAR investigation led to potent compounds, with nanomolar activity on K103N, and orally bioavailable in rats.