title: Synthesis and HMG CoA reductase inhibition of 4-thiophenyl quinolines as potential hypocholesterolemic agents.
abstract: A series of novel 4-thiophenyl quinoline-based mevalonolactone derivatives were synthesized from ethyl 6,7,8-trisubstituted-4-chloro-quinoline-3-carboxylates by several reactions and evaluated for their ability to inhibit the rat HMG CoA reductase in vitro. It was found that substitution with a variety of thiophenyl groups at position 4 in quinoline resulted in retention or enhancement of the inhibition and the preferable groups were 4-isopropyl-thiophenyl and 3-methoxy-thiophenyl. (4R,6S)-6-[(E)-2-(6,7,8-trifluoro-4-isopropylthiophenyl-quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (A16) and (4R, 6S)-6-[(E)-2-(6-fluoro-4,7-di-(3-methoxy-thiophenyl)-quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (A23) were approximately three times more potent than rosuvastatin or pitavastatin in inhibiting HMG CoA reductase and selected as the hypocholesterolemic candidates for further evaluation.
authors.affiliation: Innovation Center for Drugs, Shanghai Institute of Pharmaceutical Industry, Shanghai 200437, PR China.
authors.forename: Zhengyan
authors.initials: Z
authors.lastname: Cai
authors.forename: Weicheng
authors.initials: W
authors.lastname: Zhou
authors.forename: Lixin
authors.initials: L
authors.lastname: Sun
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010636:Phenols / Q000737:chemistry*; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013438:Sulfhydryl Compounds / Q000737:chemistry*
chemical_list: D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D010636:Phenols; D011804:Quinolines; D013438:Sulfhydryl Compounds; C042983:thiophenol; D006903:Hydroxymethylglutaryl CoA Reductases