title: Efficient synthesis of mibefradil analogues: an insight into in vitro stability.
abstract: This article describes the synthesis and biological evaluation of a chemical library of mibefradil analogues to investigate the effect of structural modification on in vitro stability. The construction of the dihydrobenzopyran structure in mibefradil derivatives 2 was achieved through two efficient approaches based on a diastereoselective intermolecular Reformatsky reaction and an intramolecular carbonyl-ene cyclization. In particular, the second strategy through the intramolecular carbonyl-ene reaction led to the formation of a key intermediate 3 in a short and highly stereoselective way, which has allowed for practical and convenient preparation of analogues 2. Using this protocol, we could obtain 22 new mibefradil analogues 2, which were biologically tested for in vitro efficacies against T-type calcium channels and metabolic stabilities. Among the synthesized compounds, we found that analogue 2aa containing a dihydrobenzopyran ring and a secondary amine linker showed high % remaining activities of the tested CYP enzymes retaining the excellent T-type calcium channel blocking activity. These findings indicated that the structural modification of 1 was effective for improving in vitro stability, i.e., reducing CYP inhibition and metabolic degradation.
authors: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, South Korea.
authors: Ji Eun
authors: JE
authors: Lee
authors: Tae Hui
authors: TH
authors: Kwon
authors: Su Jin
authors: SJ
authors: Gu
authors: Duck-Hyung
authors: DH
authors: Lee
authors: B Moon
authors: BM
authors: Kim
authors: Jae Yeol
authors: JY
authors: Lee
authors: Jae Kyun
authors: JK
authors: Lee
authors: Seon Hee
authors: SH
authors: Seo
authors: Ae Nim
authors: AN
authors: Pae
authors: Gyochang
authors: G
authors: Keum
authors: Yong Seo
authors: YS
authors: Cho
authors: Sun-Joon
authors: SJ
authors: Min
mesh_terms: D000447:Aldehydes / Q000138:chemical synthesis / Q000737:chemistry; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000378:metabolism; D002625:Chemistry, Organic / Q000379:methods*; D018360:Crystallography, X-Ray; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004355:Drug Stability; D057809:HEK293 Cells; D006801:Humans; D020748:Mibefradil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008968:Molecular Conformation
chemical_list: D000447:Aldehydes; D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D065607:Cytochrome P-450 Enzyme Inhibitors; D020748:Mibefradil; D003577:Cytochrome P-450 Enzyme System; C031000:benzimidazole