Novel amides and esters prodrugs of olmesartan: Synthesis, bioconversion, and pharmacokinetic evaluation

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 19; pp. 5895 - 5899
• Main Authors: Park, Jin-Hun, Chang, Jeong-Soo, El-Gamal, Mohammed I., Choi, Won-Kyoung, Lee, Woong San, Chung, Hye Jin, Kim, Hyun-Il, Cho, Young-Jin, Lee, Bong Sang, Jeon, Hong-Ryeol, Lee, Yong Sup, Choi, Young Wook, Lee, Jaehwi, Oh, Chang-Hyun
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-10-2010; Elsevier
• Subjects: Administration, Oral; Amide; Amides - chemistry; Animals; Antihypertensive; Antihypertensive agents; Biological and medical sciences; Cardiovascular system; Ester; Esters; General pharmacology; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacokinetics; Male; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Olmesartan; Olmesartan Medoxomil; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacokinetics; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Prodrug; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacokinetics; Rats; Rats, Sprague-Dawley; Tetrazoles - chemical synthesis; Tetrazoles - chemistry; Tetrazoles - pharmacokinetics; Antihypertensive; Ester; Amide; Olmesartan; Prodrug; Pharmacokinetics; Olmesartan medoxomil; Rat; Rodentia; Oral administration; AT1 angiotensin receptor; Metabolism; Vertebrata; Metabolic stability; Mammalia; Animal; Antihypertensive agent; Carboxamide; Sartan derivatives; Angiotensin antagonist; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.07.089

Compound
IIa was found to be well absorbed from rat gastrointestinal tract and rapidly converted into olmesartan. After oral administration of
IIa, the
C
max and AUC values of olmesartan were significantly greater than those observed after oral administration of olmesartan medoxomil. Compound
IIa is proposed to be an effective prodrug for olmesartan with improved oral bioavailability.
Synthesis of novel amides and esters prodrugs of olmesartan is described. Their in vitro stability in rat plasma was tested. The results showed that the ester derivative
IIa with
n-octyl substituted dioxolone moiety was rapidly converted into olmesartan within 30
min. The pharmacokinetic parameters of
IIa were studied and compared with those of olmesartan medoxomil. Compound
IIa is proposed to be a promising prodrug of olmesartan.