RESUMEN
The NO-sGC-cGMP signaling pathway plays an important role in the cardiovascular system. Loss of nitric oxide tone or impaired signaling has been associated with cardiovascular diseases, such as hypertension, pulmonary hypertension and heart failure. Direct activation of sGC enzyme independent of NO represents a novel approach for modulating NO signaling with tremendous therapeutic potential. Herein, we describe the design of a structurally novel class of heme-dependent sGC stimulators containing the 3,3-dimethylpyrrolidin-2-one moiety which resulted in the identification of the potent, selective stimulator 30 (MK-2947) for the treatment of hypertension.
Asunto(s)
Antihipertensivos/farmacología , Descubrimiento de Drogas , Hipertensión/tratamiento farmacológico , Guanilil Ciclasa Soluble/metabolismo , Antihipertensivos/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Amino-anthranilic acid derivatives have been identified as a new class of low serum shifted, high affinity full agonists of the human orphan G-protein-coupled receptor GPR109a with improved ADME properties.
Asunto(s)
Descubrimiento de Drogas , Receptores Acoplados a Proteínas G/agonistas , Animales , Flúor/química , Humanos , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Niacina/síntesis química , Niacina/química , Niacina/farmacología , Piridinas/síntesis química , Piridinas/química , Ratas , Ratas Sprague-Dawley , Receptores NicotínicosRESUMEN
Niacin is an effective drug for raising HDL cholesterol. However, niacin must be taken in large doses and significant side effects are often observed, including facial flushing, loss of glucose tolerance, and liver toxicity. An anthranilic acid was identified as an agonist of the niacin receptor. In order to improve efficacy and provide structural diversity, replacements for the anthranilic acid were investigated and several compounds with improved properties were identified.
Asunto(s)
Niacina/metabolismo , Receptores de Droga/metabolismo , ortoaminobenzoatos/química , Disponibilidad BiológicaRESUMEN
5-Alkyl and aryl-pyrazole-acids have been identified as a new class of selective, small-molecule, agonists of the human orphan G-protein-coupled receptor GPR109a, a high affinity receptor for the HDL-raising drug nicotinic acid.
Asunto(s)
Pirazoles/química , Receptores Acoplados a Proteínas G/agonistas , Animales , Ácidos Grasos/metabolismo , Humanos , Ratones , Niacina/química , Pirazoles/síntesis química , Pirazoles/farmacocinética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/metabolismoRESUMEN
Niacin is an effective drug for raising HDL cholesterol and reducing coronary risks, but patients show low compliance with treatment due to severe facial flushing upon taking the drug. A series of bicyclic pyrazole carboxylic acids were synthesized and tested for their ability to activate the niacin receptor. One analog, 23, showed improved potency and lacked flushing at doses that effectively altered the lipid profile of rats.
Asunto(s)
Dislipidemias/tratamiento farmacológico , Hipolipemiantes/farmacología , Niacina/farmacología , Agonistas Nicotínicos/farmacología , Pirazoles/farmacología , Animales , HDL-Colesterol/metabolismo , Ácidos Grasos no Esterificados/metabolismo , Hipolipemiantes/síntesis química , Hipolipemiantes/química , Ratones , Niacina/química , Agonistas Nicotínicos/síntesis química , Agonistas Nicotínicos/química , Pirazoles/síntesis química , Pirazoles/química , Ratas , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
5-Alkyl and aryl-pyrazole-tetrazoles have been identified as a new class of selective, small-molecule, agonists of the human G-protein-coupled receptor GPR109a, a high affinity receptor for the HDL-raising drug nicotinic acid.
Asunto(s)
Pirazoles/química , Receptores Acoplados a Proteínas G/agonistas , Tetrazoles/química , Animales , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacología , Pirazoles/farmacología , Receptores Acoplados a Proteínas G/deficiencia , Receptores Acoplados a Proteínas G/fisiología , Receptores Nicotínicos/deficiencia , Receptores Nicotínicos/fisiología , Tetrazoles/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiologíaRESUMEN
The design, synthesis, and biological activity of a series of cycloalkene acid-based niacin receptor agonists are described. This led to the discovery that tetrahydro anthranilic acid is an excellent surrogate for anthranilic acid. Several compounds were identified that were potent against the niacin receptor, had enhanced cytochrome P450 selectivity against subtypes CYP2C8 and CYP2C9, and improved oral exposure in mice.
Asunto(s)
Ciclohexenos/síntesis química , Ciclohexenos/farmacología , Ciclopentanos/síntesis química , Ciclopentanos/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Agonistas Nicotínicos/síntesis química , Agonistas Nicotínicos/farmacología , ortoaminobenzoatos/síntesis química , ortoaminobenzoatos/farmacología , Animales , Hidrocarburo de Aril Hidroxilasas/efectos de los fármacos , Ciclohexenos/química , Ciclohexenos/farmacocinética , Ciclopentanos/química , Ciclopentanos/farmacocinética , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP2C9 , Diseño de Fármacos , Humanos , Ratones , Agonistas Nicotínicos/química , Antagonistas Nicotínicos/farmacología , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacocinéticaRESUMEN
A modular, selective approach to complex α-tertiary substituted malononitriles is reported. The method takes advantage of ß-ester-substituted α,α-dinitrile alkenes as highly reactive, chemoselective electrophiles for 1,4-additions with organometallic nucleophiles to produce functionally and sterically dense all-carbon quaternary centers. In the presence of a chiral ester auxiliary bearing an aromatic ring, the 1,4-addition occurs with good to excellent selectivity due to favorable cation-π interactions. The highly functionalized malononitriles represent versatile building blocks and can be applied toward efficient, highly selective syntheses of 5,5-disubstituted pyrrolopyrimidinones.
RESUMEN
Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. Compound 1e (MK-6892) displayed excellent receptor activity, good PK across species, remarkably clean off-target profiles, good ancillary pharmacology, and superior therapeutic window over niacin regarding the FFA reduction versus vasodilation in rats and dogs.
Asunto(s)
Ácidos Carboxílicos/farmacología , Ácidos Ciclohexanocarboxílicos/farmacología , Ciclohexenos/química , Descubrimiento de Drogas , Oxadiazoles/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Área Bajo la Curva , Unión Competitiva , Células CHO , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Cricetinae , Cricetulus , Ácidos Ciclohexanocarboxílicos/química , Ácidos Ciclohexanocarboxílicos/farmacocinética , Perros , Evaluación Preclínica de Medicamentos , Ácidos Grasos no Esterificados/sangre , Humanos , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Químicos , Estructura Molecular , Oxadiazoles/química , Oxadiazoles/farmacocinética , Ratas , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Relación Estructura-Actividad , Vasodilatación/efectos de los fármacosRESUMEN
A series of HIV protease inhibitors with modifications on the P3 position have been designed and synthesized. These compounds exhibit excellent antiviral activity against both the wild type enzyme and PI-resistant clinical viral isolates. The synthesis and biological activity of the compounds are described.
Asunto(s)
Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , Línea Celular , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Humanos , Indicadores y Reactivos , Indinavir/síntesis química , Indinavir/farmacología , Relación Estructura-ActividadRESUMEN
A 1X22X41 combinatorial library or 902 compounds of indinavir analogues was synthesized on the solid support to identify a replacement for the aminoindanol moiety at P2'. 2,6-Dimethyl-4-hydroxy phenol was discovered to be a good replacement for aminoindanol.
Asunto(s)
Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/farmacología , Indinavir/análogos & derivados , Indinavir/síntesis química , Técnicas Químicas Combinatorias , Proteasa del VIH/química , Proteasa del VIH/efectos de los fármacos , Inhibidores de la Proteasa del VIH/farmacocinética , Humanos , Indicadores y Reactivos , Indinavir/farmacocinética , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
A series of highly potent HIV protease inhibitors have been designed and synthesized. These compounds are active against various clinical viral isolates as well as wild-type virus. The synthesis and biological activity of these HIV protease inhibitors are discussed.