Publication date: Available online 21 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Yoshihiro Banno, Shigekazu Sasaki, Makoto Kamata, Jun Kunitomo, Yasufumi Miyamoto, Hidenori Abe, Naohiro Taya, Satoru Oi, Masanori Watanabe, Tomoko Urushibara, Masatoshi Hazama, Shin-ichi Niwa, Saku Miyamoto, Akira Horinouchi, Ken-ichi Kuroshima, Nobuyuki Amano, Shin-ichi Matsumoto, Shinichiro Matsunaga
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 IC50 (SSTR2/SSTR5) = 0.3/>100 (nM)), was identified as a 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 (ED50 = 1.1 mg/kg) and glucose excursion in meal tolerance test in Wistar fatty diabetic rats (MED = 3.0 mg/kg) in oral administrations.Compound 3k was selected as a 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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