Novel and orally bioavailable inducible nitric oxide synthase inhibitors: synthesis and evaluation of optically active 4,5-dialkyl-2-iminoselenazolidine derivatives.
We have previously reported that (4R,5R)-5-ethyl-2-imino-4-methylthiazolidine (3) strongly inhibits inducible nitric oxide synthase (iNOS). In a successive search for strong and selective iNOS inhibitors, we, herein, describe the synthesis of the selenium analogue of 3 (4: ES-2133) and its related optically active compounds and examine their in vitro and in vivo inhibitory activity against iNOS. In addition, an alternative synthetic method to the selected compound 4 and its pharmacokinetic profile is also reported.
Ueda
Shigeo
S
Chemistry Research Laboratories, Dainippon Pharmaceutical Co., Ltd, Enoki-cho 33-94, Suita, Osaka 564-0053, Japan. shigeo-ueda@dainippon-pharm.co.jp
Terauchi
Hideo
H
Suzuki
Kenji
K
Yano
Akihiro
A
Matsumoto
Masashi
M
Kubo
Taeko
T
Minato
Hisao
H
Arai
Yukiyo
Y
Tsuji
Jun-ichi
J
Watanabe
Nobuhide
N
D001120:Arginine / Q000037:antagonists & inhibitors; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D007700:Kinetics; D008968:Molecular Conformation; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D016566:Organoselenium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D012643:Selenium / Q000737:chemistry; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D016566:Organoselenium Compounds; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D012643:Selenium