Design and synthesis of a novel series of orally active, selective somatostatin receptor 2 agonists for the treatment of type 2 diabetes

Yoshihiro Banno; Shigekazu Sasaki; Makoto KamataJun KunitomoYasufumi MiyamotoHidenori AbeNaohiro TayaSatoru OiMasanori WatanabeTomoko UrushibaraMasatoshi HazamaShin-ichi NiwaSaku MiyamotoAkira HorinouchiKen-ichi KuroshimaNobuyuki AmanoShin-ichi MatsumotoShinichiro Matsunaga

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Design and synthesis of a novel series of orally active, selective somatostatin receptor 2 agonists for the treatment of type 2 diabetes

机译：Design and synthesis of a novel series of orally active, selective somatostatin receptor 2 agonists for the treatment of type 2 diabetes

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Graphical abstract Display Omitted Abstract The discovery of a novel series of β-methyltryptophan (β MeTrp) derivatives as selective and orally active non-peptide somatostatin receptor 2 (SSTR2) agonists for the treatment of Type 2 diabetes is described. In our previous research, Compound A , β-MeTrp derivative with highly potent and selective SSTR2 agonistic activity IC 50 (SSTR2/SSTR5)=0.3/>100 (nM), was identified asa drug candidate for treatment of Type 2 diabetes which lowers significantly plasma glucose level in Wistar fatty rats in its oral administrations. However, as serious increase in AUC and phospholipidosis (PLsis) were observed in its toxicological studies in rats, follow-up compounds were searched to avoid risk of PLsis with reference to their in vitro PLsis potentials evaluated on the basis of accumulation of phospholipids in HepG2 cells exposed to the compounds. It has been found that introduction of a carbonyl group onto the piperidine and piperazine or aniline moiety of compounds A and B reduced markedly the in vitro PLsis potentials. And further modification of the compounds and their evaluation led to a discovery of compounds 3k with lower in vitro PLsis potentials exhibiting lowering effect of hypoglycemia-induced glucagon secretion in SD rats (ED 50 =1.1mg/kg) and glucose excursion in meal tolerance test in Wistar fatty diabetic rats (MED=3.0mg/kg) in oral administrations. Compound 3k was selected asa new drug candidate of selective and orally active non-peptide SSTR2 agonists for treatment of Type 2 diabetes with low in vivo PLsis potential.

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来源
《Bioorganic and medicinal chemistry》 |2017年第21期|5995-6006|共12页
作者
Yoshihiro Banno; Shigekazu Sasaki; Makoto KamataJun KunitomoYasufumi MiyamotoHidenori AbeNaohiro TayaSatoru OiMasanori WatanabeTomoko UrushibaraMasatoshi HazamaShin-ichi NiwaSaku MiyamotoAkira HorinouchiKen-ichi KuroshimaNobuyuki AmanoShin-ichi MatsumotoShinichiro Matsunaga;
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Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited;

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原文格式 PDF
正文语种英语
中图分类药学;
关键词
Non-peptide somatostatin receptor 2 agonist; β-Methyltryptophan derivatives; Phospholipidosis; Type 2 diabetes;

Design and synthesis of a novel series of orally active, selective somatostatin receptor 2 agonists for the treatment of type 2 diabetes

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