Koichi Iwanaga

Synthesis and insecticidal activity of nitroguanidine derivatives

Nitroguanidine derivatives with thiazol-5-ylmethyl moieties were prepared and their insecticidal activities against homopterous pests were tested. New synthetic routes for 2-chloro-5-chloromethylthiazole from 2,3-dichloro-1-propene and for substituted nitroguanidines from S-methyl-N-nitroisothiourea were established. Biological evaluation led to a novel insecticide (E)-1-(2-chlorothiazol-5-ylmethyl)-3-methyl-2-nitroguani dine (TI-435) which has a broad activity spectrum and is under development. ©1999 Society of Chemical Industry

Discovery of benzimidazole derivatives as orally active renin inhibitors: Optimization of 3,5-disubstituted piperidine to improve pharmacokinetic profile

We previously identified 2-tert-butyl-4-[(3-methoxypropyl)amino]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidine-5-carboxamide 3 as a potent renin inhibitor. Since 3 showed unacceptably low bioavailability (BA) in rats, structural modification, using SBDD and focused on physicochemical properties was conducted to improve its PK profile while maintaining renin inhibitory activity. Conversion of the amino group attached at the 4-position of pyrimidine to methylene group improved PK profile and decreased renin inhibitory activity. New central cores with carbon side chains were explored to improve potency. We had designed a series of 5-membered azoles and fused heterocycles that interacted with the lipophilic S3 pocket. In the course of modification, renin inhibitory activity was enhanced by the formation of an additional hydrogen bonding with the hydroxyl group of Thr77. Consequently, a series of novel benzimidazole derivatives were discovered as potent and orally bioavailable renin inhibitors. Among those, compound 13 exhibited more than five-fold of plasma renin inhibition than aliskiren in cynomolgus monkeys at dose ratio.