title: The squalestatins: synthesis and biological activity of some C3-modified analogues; replacement of a carboxylic acid or methyl ester with an isoelectronic heterocyclic functionality.
abstract: A series of squalestatins modified at the C3-position with a heterocyclic functionality was prepared and evaluated in vitro as inhibitors of squalene synthase (SQS). Structure-activity relationships for compounds with the 4,6-dimethyloctenoate at C6(S1 analogues) were different from those for analogues lacking the C6 ester (H1 analogues), with a greater dependence on the nature of the C3-substituent for the H1 series. Potent SQS inhibitory activity equivalent to that of H1 is retained by a C3-(tetrazol-5-yl) analogue, i.e., a carboxylic acid mimetic. The C3-methyl ester derivative is 10-fold less active than H1, and SQS inhibitory activity similar to that of the methyl ester was retained only in those C3-heterocycle-substituted H1 analogues for which electrostatic potential maps of the C3-substituent were closely similar to that of a methyl ester.
authors.affiliation: Glaxo Research and Development Ltd., Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Bamford
authors.forename: C
authors.initials: C
authors.lastname: Chan
authors.forename: A P
authors.initials: AP
authors.lastname: Craven
authors.forename: B W
authors.initials: BW
authors.lastname: Dymock
authors.forename: D
authors.initials: D
authors.lastname: Green
authors.forename: R A
authors.initials: RA
authors.lastname: Henson
authors.forename: B E
authors.initials: BE
authors.lastname: Kirk
authors.forename: M G
authors.initials: MG
authors.lastname: Lester
authors.forename: P A
authors.initials: PA
authors.lastname: Procopiou
authors.forename: M A
authors.initials: MA
authors.lastname: Snowden
mesh_terms: D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004952:Esters / Q000737:chemistry; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003904:Mitosporic Fungi / Q000378:metabolism; D008958:Models, Molecular; D051381:Rats; D013329:Structure-Activity Relationship; D014233:Tricarboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004952:Esters; D014233:Tricarboxylic Acids; C075117:squalestatin 1; D013186:Farnesyl-Diphosphate Farnesyltransferase