Novel pyrrole- and 1,2,3-triazole-based 2,3-oxidosqualene cyclase inhibitors.
Pyrrole- and 1,2,3-triazole-based 2,3-oxidosqualene cyclase (OSC) inhibitors 3 and 4 were discovered by conducting a virtual screening, a docking study based on the crystallographic structure of OSC, and biological assays. The hit rate of the assays was increased by establishing appropriate substructural filters in the virtual screening stage. Amide derivatives of 8 and 12 preserved the inhibitory activity of parent compound 3, which provided a reasonable starting point for further structure-activity-relationship (SAR) studies on related compounds.
Watanabe
Takumi
T
Institute of Microbial Chemistry, Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan. twatanabe@bikaken.or.jp
Umezawa
Yoji
Y
Takahashi
Yoshikazu
Y
Akamatsu
Yuzuru
Y
D001665:Binding Sites; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011758:Pyrroles / Q000737:chemistry*; D013185:Squalene / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
C002821:2,3-oxidosqualene; D004791:Enzyme Inhibitors; D011758:Pyrroles; D014230:Triazoles; D013185:Squalene; D019751:Intramolecular Transferases; C021924:lanosterol synthase