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
The preparation of a series of substituted indoles coupled to six- and seven-membered cyclic lactams is described and their role as human glycogen phosphorylase a inhibitors discussed. The SAR of the indole moiety and lactam ring are presented.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Glucógeno Fosforilasa/antagonistas & inhibidores , Quinolinas/síntesis química , Quinolinas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Cinética , Modelos Moleculares , Conformación Molecular , Quinolinas/química , Relación Estructura-ActividadRESUMEN
Preparation and screening of mixture libraries based on a 2-arylindole scaffold resulted in the discovery of potent ligands for a variety of G-protein coupled receptors.
Asunto(s)
Técnicas Químicas Combinatorias , Indoles/síntesis química , Indoles/farmacología , Receptores de Superficie Celular/metabolismo , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Aminas/síntesis química , Aminas/química , Aminas/farmacología , Unión Competitiva/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Proteínas de Unión al GTP , Humanos , Indoles/química , Ligandos , Receptores de Quimiocina/metabolismo , Receptores de Serotonina/metabolismo , Receptores de Taquicininas/metabolismo , Relación Estructura-ActividadRESUMEN
A new class of 4-(aminoheterocycle)piperidine derived 1,3,4 trisubstituted pyrrolidine CCR5 antagonists is reported. Compound 4a is shown to have good binding affinity (1.8 nM) and antiviral activity in PBMC's (IC(95)=50 nM). Compound 4a also has improved PK properties relative to 1.
Asunto(s)
Antagonistas de los Receptores CCR5 , Piperidinas/síntesis química , Piperidinas/farmacología , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Animales , Fármacos Anti-VIH/síntesis química , Células CHO , Quimiocina CCL4 , Cricetinae , Semivida , Células HeLa , Humanos , Enlace de Hidrógeno , Proteínas Inflamatorias de Macrófagos/metabolismo , Piperidinas/farmacocinética , Pirrolidinas/farmacocinética , RatasRESUMEN
The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones, gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacokinetics.