RESUMO
The calcium-sensing receptor (CaSR) plays an important role in sensing extracellular calcium ions and regulating parathyroid hormone secretion by parathyroid gland cells, and the receptor is a suitable target for the treatment of hyperparathyroidism. Cinacalcet hydrochloride is a representative CaSR agonist which widely used for the hyperparathyroidism. However, it has several issues to clinical use, such as nausea/vomiting and strong inhibition of CYP2D6. We tried to improve these issues of cinacalcet for a new pharmaceutical agent as a preferable CaSR agonist. Optimization from cinacalcet resulted in the identification of pyrrolidine compounds and successfully led to the discovery of evocalcet as an oral allosteric CaSR agonist. Evocalcet, which exhibited highly favorable profiles such as CaSR agonistic activity and good DMPK profiles, will provide a novel therapeutic option for secondary hyperparathyroidism.
Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Descoberta de Drogas , Hiperparatireoidismo/tratamento farmacológico , Pirrolidinas/farmacologia , Receptores de Detecção de Cálcio/agonistas , Animais , Inibidores das Enzimas do Citocromo P-450/síntese química , Inibidores das Enzimas do Citocromo P-450/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
A novel series of furan-2-one and pyrrolin-2-one derivatives having PAI-1 (plasminogen activator inhibitor-1) inhibitory activity were synthesized and evaluated for their antithrombotic activity in a rat arterial thrombosis model. Among the synthesized compounds, 5f (T-1776Na) was found to have good selectivity for PAI-1 over other enzymes and high antithrombotic activity.
Assuntos
Fibrinolíticos/síntese química , Inibidor 1 de Ativador de Plasminogênio/química , Pirróis/síntese química , Pirrolidinas/síntese química , Animais , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Humanos , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Pirróis/química , Pirróis/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Novel 1,7- and 2,7-naphthyridine derivatives, designed by the introduction of nitrogen atom into the phenyl ring of previously reported 4-aryl-1-isoquinolinone derivatives, were disclosed as a new structural class of potent and specific PDE5 inhibitors. Among them, 2,7-naphthyridine 4c showed potent PDE5 inhibition (IC(50)=0.23 nM) and one of the best PDE5 specificities against PDEs1-4,6 (>100,000-fold selective versus PDE1-4, 240-fold selective vs PDE6). This compound showed more potent relaxant effects on isolated rabbit corpus cavernosum (EC(30)=5.0 nM) than Sildenafil (EC(30)=8.7 nM). The compound 4c (T-0156) was selected for further biological and pharmacological evaluation of erectile dysfunction.
Assuntos
Naftiridinas/síntese química , Naftiridinas/farmacologia , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/efeitos dos fármacos , 3',5'-GMP Cíclico Fosfodiesterases , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Genitália Masculina/efeitos dos fármacos , Técnicas In Vitro , Indicadores e Reagentes , Isoenzimas/antagonistas & inibidores , Masculino , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Piperazinas/farmacologia , Purinas , Coelhos , Citrato de Sildenafila , Relação Estrutura-Atividade , SulfonasRESUMO
Cis- and trans-isomers of alpha-hydroxy-alpha,beta-dibenzyl-gamma-butyrolactone lignans 1a,d-g and 2a,c,d were stereoselectively synthesized in good yields based on the electrophilic addition to the metal enolate of alpha-benzyl-gamma-butyrolactone derivatives 1l-o and 3 as a key step. This method was applied to the syntheses of (+/-)-trachelogenin and (+/-)-guayadequiol, representative examples of the trans- and cis-isomers of alpha-hydroxy-alpha,beta-dibenzyl-gamma-butyrolactone lignan series.