RESUMO
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.
Assuntos
Anti-Hipertensivos/farmacologia , Descoberta de Drogas , Hipertensão/tratamento farmacológico , Guanilil Ciclase Solúvel/metabolismo , Anti-Hipertensivos/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
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.
RESUMO
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.
Assuntos
Descoberta de Drogas , Receptores Acoplados a Proteínas G/agonistas , Animais , Flúor/química , Humanos , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Niacina/síntese química , Niacina/química , Niacina/farmacologia , Piridinas/síntese química , Piridinas/química , Ratos , Ratos Sprague-Dawley , Receptores NicotínicosRESUMO
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.
Assuntos
Pirazóis/química , Receptores Acoplados a Proteínas G/agonistas , Animais , Ácidos Graxos/metabolismo , Humanos , Camundongos , Niacina/química , Pirazóis/síntese química , Pirazóis/farmacocinética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/metabolismoRESUMO
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.
Assuntos
Niacina/metabolismo , Receptores de Droga/metabolismo , ortoaminobenzoatos/química , Disponibilidade BiológicaRESUMO
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.
Assuntos
Ácidos Carboxílicos/farmacologia , Ácidos Cicloexanocarboxílicos/farmacologia , Cicloexenos/química , Descoberta de Drogas , Oxidiazóis/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Área Sob a Curva , Ligação Competitiva , Células CHO , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Cricetinae , Cricetulus , Ácidos Cicloexanocarboxílicos/química , Ácidos Cicloexanocarboxílicos/farmacocinética , Cães , Avaliação Pré-Clínica de Medicamentos , Ácidos Graxos não Esterificados/sangue , Humanos , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Químicos , Estrutura Molecular , Oxidiazóis/química , Oxidiazóis/farmacocinética , Ratos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Relação Estrutura-Atividade , Vasodilatação/efeitos dos fármacosRESUMO
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.
Assuntos
Dislipidemias/tratamento farmacológico , Hipolipemiantes/farmacologia , Niacina/farmacologia , Agonistas Nicotínicos/farmacologia , Pirazóis/farmacologia , Animais , HDL-Colesterol/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Hipolipemiantes/síntese química , Hipolipemiantes/química , Camundongos , Niacina/química , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/química , Pirazóis/síntese química , Pirazóis/química , Ratos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismoRESUMO
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.
Assuntos
Pirazóis/química , Receptores Acoplados a Proteínas G/agonistas , Tetrazóis/química , Animais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacologia , Pirazóis/farmacologia , Receptores Acoplados a Proteínas G/deficiência , Receptores Acoplados a Proteínas G/fisiologia , Receptores Nicotínicos/deficiência , Receptores Nicotínicos/fisiologia , Tetrazóis/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
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.
Assuntos
Cicloexenos/síntese química , Cicloexenos/farmacologia , Ciclopentanos/síntese química , Ciclopentanos/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/farmacologia , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/farmacologia , Animais , Hidrocarboneto de Aril Hidroxilases/efeitos dos fármacos , Cicloexenos/química , Cicloexenos/farmacocinética , Ciclopentanos/química , Ciclopentanos/farmacocinética , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP2C9 , Desenho de Fármacos , Humanos , Camundongos , Agonistas Nicotínicos/química , Antagonistas Nicotínicos/farmacologia , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacocinéticaRESUMO
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.
Assuntos
Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Linhagem Celular , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Indicadores e Reagentes , Indinavir/síntese química , Indinavir/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Fármacos Anti-HIV/síntese química , Inibidores da Protease de HIV/síntese química , Aminas , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Desenho de Fármacos , Inibidores da Protease de HIV/farmacologia , Compostos Heterocíclicos , Humanos , Concentração Inibidora 50 , Mutação , Oligopeptídeos/síntese química , Oligopeptídeos/farmacologia , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
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.