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
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
We describe an extensive SAR study in the 6-[4-fluoro-3-(substituted)benzyl]-4,5-dimethylpyridazin-3(2H)-one series which led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, and displaying >100-fold selectivity over the BRCA wild type counterparts. The series of compounds was devoid of hERG channel activity, and CYP inhibition and induction liabilities. Several analogs were stable in rat and human liver microsomes and displayed moderate rat clearance, with urinary excretion of parent as the major route of elimination.
Asunto(s)
Proteína BRCA1/deficiencia , Piperazinas/síntesis química , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Piridazinas/síntesis química , Animales , Proteína BRCA1/genética , Células HeLa , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Piperazinas/metabolismo , Piperazinas/farmacología , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/metabolismo , Piridazinas/metabolismo , Piridazinas/farmacología , RatasRESUMEN
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
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
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
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
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
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
5-(Trifluoroacetyl)thiophene-2-carboxamides were found to be potent and selective class II HDAC inhibitors. This paper describes their further development and the investigation on the cause for the lack of cell-based activity. A rapid screening assay was set up which enabled the identification of more metabolic stable compounds as potent and selective class II HDAC inhibitors.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Inhibidores de Histona Desacetilasas , Tiofenos/síntesis química , Tiofenos/farmacología , Amidas/química , Hidrocarburo de Aril Hidroxilasas/antagonistas & inhibidores , Citocromo P-450 CYP2C9 , Diseño de Fármacos , Células HCT116 , Células HeLa , Hepatocitos/efectos de los fármacos , Histona Desacetilasas/clasificación , Humanos , Microsomas Hepáticos/efectos de los fármacos , Estructura Molecular , Relación Estructura-Actividad , Tiofenos/química , Tubulina (Proteína)/efectos de los fármacosRESUMEN
Human immunodeficiency virus type-1 (HIV-1) integrase, one of the three constitutive viral enzymes required for replication, is a rational target for chemotherapeutic intervention in the treatment of AIDS that has also recently been confirmed in the clinical setting. We report here on the design and synthesis of N-benzyl-5,6-dihydroxypyrimidine-4-carboxamides as a class of agents which exhibits potent inhibition of the HIV-integrase-catalyzed strand transfer process. In the current study, structural modifications on these molecules were made in order to examine effects on HIV-integrase inhibitory potencies. One of the most interesting compounds for this series is 2-[1-(dimethylamino)-1-methylethyl]-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide 38, with a CIC95 of 78 nM in the cell-based assay in the presence of serum proteins. The compound has favorable pharmacokinetic properties in preclinical species (rats, dogs, and monkeys) and shows no liabilities in several counterscreening assays, highlighting its potential as a clinically useful antiviral agent.
Asunto(s)
Inhibidores de Integrasa VIH/síntesis química , VIH-1/efectos de los fármacos , Piridinas/síntesis química , Pirimidinas/síntesis química , Animales , Disponibilidad Biológica , Proteínas Sanguíneas/metabolismo , Línea Celular Tumoral , Perros , Inhibidores de Integrasa VIH/farmacocinética , Inhibidores de Integrasa VIH/farmacología , Semivida , Humanos , Macaca mulatta , Unión Proteica , Piridinas/química , Piridinas/farmacología , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas , Relación Estructura-Actividad , Replicación ViralRESUMEN
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
The dihydroxypyrimidine carboxamide 4a was discovered as a potent and selective HIV integrase strand transfer inhibitor. The optimization of physicochemical properties, pharmacokinetic profiles, and potency led to the identification of 13 in the dihydroxypyrimidine series and 18 in the N-methylpyrimidinone series having low nanomolar activity in the cellular HIV spread assay in the presence of 50% normal human serum and very good pharmacokinetics in preclinical species.
Asunto(s)
Amidas/síntesis química , Inhibidores de Integrasa VIH/síntesis química , Pirimidinas/síntesis química , Administración Oral , Amidas/química , Amidas/farmacología , Animales , Disponibilidad Biológica , Perros , Inhibidores de Integrasa VIH/farmacocinética , Inhibidores de Integrasa VIH/farmacología , VIH-1/efectos de los fármacos , Humanos , Técnicas In Vitro , Macaca mulatta , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinonas/síntesis química , Pirimidinonas/farmacocinética , Pirimidinonas/farmacología , Ratas , Suero , Relación Estructura-Actividad , Replicación ViralRESUMEN
A strategy to obtain a fully orthogonal estrogen-receptor-based gene switch responsive to molecules with acceptable pharmacological properties is presented. From a series of tetrahydrofluorenones active on the wild-type estrogen receptor (ER) an inactive analogue is chosen as a new lead compound. Coevolution of receptor mutants and ligands leads to an ER-based gene switch suitable for studies in animal models.
Asunto(s)
Fluorenos/síntesis química , Receptores de Estrógenos/efectos de los fármacos , Sitios de Unión , Estradiol/química , Receptor alfa de Estrógeno/efectos de los fármacos , Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/efectos de los fármacos , Receptor beta de Estrógeno/genética , Fluorenos/química , Fluorenos/farmacología , Células HeLa , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Mutación , Receptores de Estrógenos/genética , Relación Estructura-ActividadRESUMEN
It is highly desirable to design ligand-dependent transcription regulation systems based on transactivators unresponsive to endogenous ligands but induced by synthetic small molecules unable to activate endogenous receptors. Using molecular modeling and yeast selection, we identified an estrogen receptor ligand binding domain double mutant (L384M, M421G) with decreased affinity to estradiol and enhanced binding to compounds inactive on estrogen receptors. Nonresponsiveness to estrogen was achieved by additionally adding the G521R substitution while introducing an "antagonistic-type" side chain in the compound, as in 4-hydroxytamoxifen. The triple-substituted ligand binding domain is insensitive to physiological concentrations of estradiol and has nanomolar affinity for the ligand. In this binary system, both receptor and ligand are, therefore, reciprocally specific. The mutated variant in the context of a chimeric transcription factor provides tight, ligand-dependent regulation of reporter gene expression.
Asunto(s)
Estradiol/análogos & derivados , Receptor alfa de Estrógeno/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Transcripción Genética , Sustitución de Aminoácidos , Sitios de Unión/genética , Diseño de Fármacos , Estradiol/metabolismo , Estradiol/farmacología , Receptor alfa de Estrógeno/genética , Genes Reporteros , Humanos , Cinética , Ligandos , Proteínas Recombinantes de Fusión/genética , Factores de Transcripción/genética , Levaduras/genéticaRESUMEN
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
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
LasR regulates toxin production in Pseudomonas aeruginosa and its inhibition can attenuate the virulence of this opportunistic human pathogen. To aid studies of interactions with inhibitors, we report the NMR backbone assignments for the dimeric LasR ligand-binding domain.
Asunto(s)
Proteínas Bacterianas/química , Espectroscopía de Resonancia Magnética/métodos , Pseudomonas aeruginosa/metabolismo , Transactivadores/química , Secuencia de Aminoácidos , Isótopos de Carbono/química , Peso Molecular , Isótopos de Nitrógeno/química , Estructura Terciaria de Proteína , ProtonesRESUMEN
Many Gram-negative bacteria communicate via molecules called autoinducers to coordinate the activities of their populations. Such communication is termed quorum sensing and can regulate pathogenic virulence factor production and antimicrobial resistance. The quorum sensing system of Pseudomonas aeruginosa is currently the most intensively researched, because this bacterium is an opportunistic human pathogen annually responsible for the death of thousands of cystic fibrosis sufferers and many other immunocompromised individuals. Quorum sensing inhibitors can attenuate the pathogenicity of P. aeruginosa. Here we present the crystal structure of the P. aeruginosa LasR ligand-binding domain bound to its autoinducer 3-oxo-C(12)-acylhomoserine lactone. The structure is a symmetrical dimer, with each monomer exhibiting an alpha-beta-alpha fold similar to the TraR and SdiA quorum sensing proteins of Agrobacterium tumefaciens and Escherichia coli. The structure was determined up to 1.8-A resolution and reveals the atomic interactions between LasR and its autoinducer. The monomer structures of LasR, TraR, and SdiA are comparable but display differences in their quaternary organization. Inspection of their binding sites shows some unexpected variations resulting in quite different conformations of their bound autoinducers. We modeled interactions between LasR and various quorum sensing inhibitors, yielding insight into their possible mechanisms of action. The structure also provides a platform for the optimization, or de novo design, of quorum sensing inhibitors.
Asunto(s)
4-Butirolactona/análogos & derivados , Proteínas Bacterianas/química , Proteínas de Unión al ADN/química , Lactonas/química , Pseudomonas aeruginosa/química , Percepción de Quorum , Transactivadores/química , Factores de Virulencia/química , 4-Butirolactona/química , 4-Butirolactona/metabolismo , Proteínas Bacterianas/metabolismo , Cristalografía por Rayos X , Fibrosis Quística/complicaciones , Fibrosis Quística/metabolismo , Fibrosis Quística/mortalidad , Proteínas de Unión al ADN/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Humanos , Infecciones Oportunistas/etiología , Infecciones Oportunistas/metabolismo , Infecciones Oportunistas/mortalidad , Estructura Terciaria de Proteína , Infecciones por Pseudomonas/etiología , Infecciones por Pseudomonas/metabolismo , Infecciones por Pseudomonas/mortalidad , Pseudomonas aeruginosa/metabolismo , Pseudomonas aeruginosa/patogenicidad , Percepción de Quorum/fisiología , Homología Estructural de Proteína , Transactivadores/metabolismo , Factores de Virulencia/metabolismoRESUMEN
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.