RESUMEN
Smoothened (Smo) antagonists are emerging as new therapies for the treatment of neoplasias with aberrantly reactivated hedgehog (Hh) signaling pathway. A novel series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as smoothened antagonists was recently described, herein the series has been further optimized through the incorporation of a basic amine into the urea. This development resulted in identification of some exceptionally potent smoothened antagonists with low serum shifts, however, reductive ring opening on the 1,2,4-oxadiazole in rats limits the applicability of these compounds in in vivo studies.
Asunto(s)
Amidas/farmacología , Piperazinas/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Receptor Smoothened , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The Hedgehog (Hh-) signaling pathway is a key developmental pathway which gets reactivated in many human tumors, and smoothened (Smo) antagonists are emerging as novel agents for the treatment of malignancies dependent on the Hh-pathway, with the most advanced compounds demonstrating encouraging results in initial clinical trials. A novel series of potent bicyclic hydantoin Smo antagonists was reported in the preceding article, these have been resolved, and optimized to identify potent homochiral derivatives with clean off-target profiles and good pharmacokinetic properties in preclinical species. While showing in vivo efficacy in mouse allograft models, unsubstituted bicyclic tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-diones were shown to epimerize in plasma. Alkylation of the C-8 position blocks this epimerization, resulting in the identification of MK-5710 (47) which was selected for further development.
Asunto(s)
Antineoplásicos/química , Proteínas Hedgehog/antagonistas & inhibidores , Imidazoles/química , Pirazinas/química , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Perros , Proteínas Hedgehog/metabolismo , Humanos , Imidazoles/farmacología , Imidazoles/uso terapéutico , Ratones , Neoplasias/tratamiento farmacológico , Pirazinas/farmacología , Pirazinas/uso terapéutico , Ratas , Transducción de Señal/efectos de los fármacos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain. Structure-activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate. The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.
Asunto(s)
Antivirales/síntesis química , Hepacivirus/efectos de los fármacos , Indoles/síntesis química , Oxazocinas/síntesis química , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Disponibilidad Biológica , Línea Celular Tumoral , Cristalografía por Rayos X , Perros , Hepacivirus/enzimología , Hepacivirus/fisiología , Humanos , Indoles/farmacocinética , Indoles/farmacología , Macaca mulatta , Ratones , Ratones SCID , Ratones Transgénicos , Modelos Moleculares , Estructura Molecular , Oxazocinas/farmacocinética , Oxazocinas/farmacología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Viremia/tratamiento farmacológico , Viremia/virología , Replicación Viral/efectos de los fármacosRESUMEN
5-Aryl-2-(trifluoroacetyl)thiophenes were identified as a new series of class II HDAC inhibitors (HDACi). Further development of this new series led to compounds such as 6h, a potent inhibitor of HDAC4 and HDAC6 (HDAC4 WT IC(50) = 310 nM, HDAC6 IC(50) = 70 nM) that displays 40-fold selectivity over HDAC1 and improved stability in HCT116 cancer cells (t(1/2) = 11 h). Compounds 6h and 2 show inhibition of alpha-tubulin deacetylation in HCT116 cells at 1 microM concentration and antiproliferation effects only at concentrations where inhibition of histone H3 deacetylation is observed.
Asunto(s)
Antineoplásicos/síntesis química , Histona Desacetilasa 2/antagonistas & inhibidores , Proteínas Represoras/antagonistas & inhibidores , Tiofenos/síntesis química , Acetilación , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasa 6 , Histona Desacetilasas/metabolismo , Histonas/metabolismo , Humanos , Isoenzimas/antagonistas & inhibidores , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacología , Tubulina (Proteína)/metabolismoRESUMEN
We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADP-ribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC(50) = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC(50) = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC(50) in the 10-100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.
Asunto(s)
Amidas/farmacología , Descubrimiento de Drogas , Genes BRCA1 , Genes BRCA2 , Indazoles/farmacología , Mutación , Neoplasias/genética , Piperidinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Administración Oral , Amidas/administración & dosificación , Amidas/química , Amidas/farmacocinética , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica , Estabilidad de Medicamentos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Indazoles/administración & dosificación , Indazoles/química , Indazoles/farmacocinética , Concentración 50 Inhibidora , Neoplasias/enzimología , Neoplasias/patología , Piperidinas/administración & dosificación , Piperidinas/química , Piperidinas/farmacocinética , RatasRESUMEN
In a follow-up to our recent disclosure of P2-P4 macrocyclic inhibitors of the hepatitis C virus (HCV) NS3 protease (e.g., 1, Chart 1), we report a new but related compound series featuring a basic amine at the N-terminus of the P3-amino acid residue. Replacement of the electroneutral P3-amino acid capping group (which is a feature of almost all tripeptide-like inhibitors of NS3 reported to date) with a basic group is not only tolerated but can result in advantageous cell based potency. Optimization of this new class of P3-amine based inhibitors gave compounds such as 25 and 26 that combine excellent cell based activity with pharmacokinetic properties that are attractive for an antiviral targeting HCV.
Asunto(s)
Aminas/síntesis química , Antivirales/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Aminas/farmacocinética , Aminas/farmacología , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Perros , Descubrimiento de Drogas , Masculino , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
We report the synthesis and biological evaluation of N-[(1-aryl-1H-indazol-5-yl)methyl]amide derivatives as Smoothened antagonists and inhibitors of the Hedgehog pathway. Identification of the lead structure 1 by HTS, followed by SAR study on the amide and aryl portions led to the discovery of antagonists with nanomolar activity.
Asunto(s)
Amidas/síntesis química , Indazoles/síntesis química , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/química , Amidas/farmacología , Catálisis , Línea Celular , Química Farmacéutica/métodos , Técnicas Químicas Combinatorias/métodos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Indazoles/farmacología , Concentración 50 Inhibidora , Modelos Químicos , Transducción de Señal , Receptor Smoothened , Relación Estructura-ActividadRESUMEN
PARP inhibitors have been demonstrated to retard intracellular DNA repair and therefore sensitize tumor cells to cytotoxic agents or ionizing radiation. We report the identification of a novel class of PARP1 inhibitors, containing a pyrrolo moiety fused to a dihydroisoquinolinone, derived from virtual screening of the proprietary collection. SAR exploration around the nitrogen of the aminoethyl appendage chain of 1 led to compounds that displayed low nanomolar activity in a PARP1 enzymatic assay.
Asunto(s)
Inhibidores de Poli(ADP-Ribosa) Polimerasas , Quinolonas/química , Antineoplásicos/farmacología , Sitios de Unión , Química Farmacéutica/métodos , Cristalografía por Rayos X/métodos , Reparación del ADN , Diseño de Fármacos , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Ligandos , Modelos Químicos , Polímeros/química , Relación Estructura-ActividadRESUMEN
A novel series of pyrazolo[1,5-a]quinazolin-5(4H)-one derivatives proved to be a potent class of PARP-1 inhibitors. An extensive SAR around the 3-position of pyrazole in the scaffold led to the discovery of amides derivatives as low nanomolar PARP-1 inhibitors.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Pirazoles/síntesis química , Amidas/química , Química Orgánica/métodos , Química Farmacéutica/métodos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacología , Células HeLa , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Estructura Molecular , Pirazoles/farmacología , Quinazolinonas/síntesis química , Quinazolinonas/farmacología , Relación Estructura-ActividadRESUMEN
Trifluoroacetylthiophene carboxamides have recently been reported to be class II HDAC inhibitors, with moderate selectivity. Exploration of replacements for the carboxamide with bioisosteric pentatomic heteroaromatic like 1,3,4-oxadiazoles, 1,2,4-oxadiazoles and 1,3-thiazoles, led to the discovery that 2-trifluoroacetylthiophene 1,3,4-oxadiazole derivatives are very potent low nanomolar HDAC4 inhibitors, highly selective over class I HDACs (HDAC 1 and 3), and moderately stable in HCT116 cell culture.
Asunto(s)
Inhibidores de Histona Desacetilasas , Oxadiazoles/síntesis química , Oxadiazoles/farmacología , Tiofenos/síntesis química , Tiofenos/farmacología , Técnicas Químicas Combinatorias , Diseño de Fármacos , Células HCT116 , Histona Acetiltransferasas/antagonistas & inhibidores , Histona Desacetilasas/clasificación , Humanos , Estructura Molecular , Oxadiazoles/química , Relación Estructura-Actividad , Tiofenos/químicaRESUMEN
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.