Discovery of olmesartan hexetil: A new potential prodrug of olmesartan

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 5; pp. 1347 - 1350
• Main Authors: El-Gamal, Mohammed I., Anbar, Hanan S., Chung, Hye Jin, Kim, Hyun-Il, Cho, Young-Jin, Lee, Bong Sang, Lee, Sun Ahe, Moon, Ji Yun, Lee, Dong Jin, Kwon, Dow, Choi, Won-Jai, Jeon, Hong-Ryeol, Oh, Chang-Hyun
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.03.2013; Elsevier
• Subjects: Angiotensin II Type 1 Receptor Blockers - chemical synthesis; Angiotensin II Type 1 Receptor Blockers - pharmacokinetics; Animals; Antihypertensive; Antihypertensive Agents - pharmacokinetics; bioavailability; Biological Availability; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Discovery; Drug Stability; Ester; Esters - chemical synthesis; gastric juice; Gastric Juice - chemistry; Gastric Juice - metabolism; Imidazoles - blood; Imidazoles - chemical synthesis; Imidazoles - pharmacokinetics; Life Sciences & Biomedicine; liver microsomes; Male; Microsomes, Liver - metabolism; Olmesartan hexetil; Olmesartan medoxomil; Pharmacokinetics; Pharmacology & Pharmacy; Physical Sciences; Prodrug; Prodrugs - chemical synthesis; Prodrugs - pharmacokinetics; Rats; Rats, Sprague-Dawley; Science & Technology; Tetrazoles - blood; Tetrazoles - chemical synthesis; Tetrazoles - pharmacokinetics; Antihypertensive; Ester; Prodrug; Olmesartan hexetil; Pharmacokinetics; Olmesartan medoxomil; BIOACTIVATING HYDROLASE; RENIN; ACIDS; II RECEPTOR ANTAGONISTS; MEDOXOMIL; ANGIOTENSIN-CONVERTING ENZYME; BLOCKER
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.12.090

Synthesis of a new ester prodrug of olmesartan, olmesartan hexetil (1), is described. It is in vitro stabilities and in vivo pharmacokinetics (PK) were evaluated. It showed high stability in simulated gastric juice, and was rapidly hydrolyzed to olmesartan in rat liver microsomes and rat plasma in vitro. Cmax and AUClast for olmesartan were significantly increased in case of hexetil prodrug, compared with olmesartan medoxomil. Olmesartan hexetil is proposed to be an efficient prodrug of olmesartan with markedly increased oral bioavailability.