Synthesis and evaluation of atorvastatin esters as prodrugs metabolically activated by human carboxylesterases

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 3; pp. 921 - 923
• Main Authors: Mizoi, Kenta, Takahashi, Masato, Haba, Masami, Hosokawa, Masakiyo
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.02.2016; Elsevier
• Subjects: Atorvastatin; Atorvastatin Calcium - chemical synthesis; Atorvastatin Calcium - chemistry; Atorvastatin Calcium - metabolism; Carboxylesterase; Carboxylic Acids - chemistry; Carboxylic Ester Hydrolases - metabolism; CES1; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Esters - metabolism; Humans; Life Sciences & Biomedicine; Liver - metabolism; Metabolism; Microsomes - metabolism; Pharmacology & Pharmacy; Physical Sciences; Prodrug; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - metabolism; Science & Technology; THF; EDC; DMP; DMAP; Atorvastatin; Prodrug; Carboxylesterase; Metabolism; TsOH; CES1; REDUCTASE INHIBITORS; ASYMMETRIC-SYNTHESIS; CPT-11 HYDROLYSIS; SPECIFICITY; SIDE-CHAIN; IDENTIFICATION; HCE-1; HUMAN LIVER; CDNA CLONING; EXPRESSION
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.12.069

[Display omitted] We synthesized 11 kinds of prodrug with an esterified carboxylic acid moiety of atorvastatin in moderate to high yields. We discovered that they underwent metabolic activation specifically by the human carboxylesterase 1 (CES1) isozyme. The results suggested that these ester compounds of atorvastatin have the potential to act as prodrugs in vivo.