Discovery of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid diamides that increase CFTR mediated chloride transport.
A series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid diamides that increase chloride transport in cells expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein has been identified from our compound library. Analoging efforts and the resulting structure-activity relationships uncovered are detailed. Compound potency was improved over 30-fold from the original lead, yielding several analogs with EC(50) values below 10nM in our cellular chloride transport assay.
Hirth
Bradford H
BH
Genzyme Drug Discovery and Development, Genzyme Corp., One Kendall Sq., Cambridge, MA 02139, USA. bradford.hirth@genzyme.com <bradford.hirth@genzyme.com>
Qiao
Shuang
S
Cuff
Lisa M
LM
Cochran
Brian M
BM
Pregel
Marko J
MJ
Gregory
Jill S
JS
Sneddon
Scott F
SF
Kane
John L
JL
D000577:Amides / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002712:Chlorides / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D017136:Ion Transport; D051379:Mice; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000378:metabolism
D000577:Amides; D002712:Chlorides; D044005:Tetrahydroisoquinolines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C078986:1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid