RESUMO
The discovery of reldesemtiv, a second-generation fast skeletal muscle troponin activator (FSTA) that increases force production at submaximal stimulation frequencies, is reported. Property-based optimization of high throughput screening hit 1 led to compounds with improved free exposure and in vivo muscle activation potency compared to the first-generation FSTA, tirasemtiv. Reldesemtiv demonstrated increased muscle force generation in a phase 1 clinical trial and is currently being evaluated in clinical trials for the treatment of amyotrophic lateral sclerosis.
Assuntos
Descoberta de Drogas , Músculo Esquelético/efeitos dos fármacos , Troponina/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Relação Estrutura-AtividadeRESUMO
Although antiretroviral therapies have been effective in decreasing active viral loads in AIDS patients, the persistence of latent viral reservoirs prevents eradication of the virus. Prostratin and DPP (12-deoxyphorbol-13-phenylacetate) activate the latent virus and thus represent promising adjuvants for antiviral therapy. Their limited supply and the challenges of accessing related structures have, however, impeded therapeutic development and the search for clinically superior analogs. Here we report a practical synthesis of prostratin and DPP starting from phorbol or crotophorbolone, agents readily available from renewable sources, including a biodiesel candidate. This synthesis reliably supplies gram quantities of the therapeutically promising natural products, hitherto available only in low and variable amounts from natural sources, and opens access to a variety of new analogs.
Assuntos
Fármacos Anti-HIV/síntese química , HIV-1/efeitos dos fármacos , Ésteres de Forbol/síntese química , Quimioterapia Adjuvante , HIV-1/fisiologia , Humanos , Modelos Moleculares , Forbóis/química , Carga Viral , Latência Viral/efeitos dos fármacosRESUMO
[reaction: see text] The tandem oxy-Cope/ene/Claisen rearrangement has been developed in our laboratory as a powerful method for rapid construction of complex Decalin cores. Herein, we describe the use of this method to generate the Decalin core of the natural antibiotic tetrodecamycin (1) bearing six contiguous stereocenters.
