Discovery of evocalcet, a next-generation calcium-sensing receptor agonist for the treatment of hyperparathyroidism.

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.

Synthesis and evaluation of pyrrolin-2-one compounds, a series of plasminogen activator inhibitor-1 inhibitors.

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.

1,7- and 2,7-naphthyridine derivatives as potent and highly specific PDE5 inhibitors.

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).

Stereoselective Syntheses of Cis- and Trans-Isomers of alpha-Hydroxy-alpha,beta-dibenzyl-gamma-butyrolactone Lignans: New Syntheses of (+/-)-Trachelogenin and (+/-)-Guayadequiol.

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.