1-BENZYLSPIRO[PIPERIDINE-4,1'-PYRIDO[3,4-b]indole] 'co-potentiators' for minimal function CFTR mutants.
We previously identified a spiro [piperidine-4,1-pyrido [3,4-b]indole] class of co-potentiators that function in synergy with existing CFTR potentiators such as VX-770 or GLGP1837 to restore channel activity of a defined subset of minimal function cystic fibrosis transmembrane conductance regulator (CFTR) mutants. Here, structure-activity studies were conducted to improve their potency over the previously identified compound, 20 (originally termed CP-A01). Targeted synthesis of 37 spiro [piperidine-4,1-pyrido [3,4-b]indoles] was generally accomplished using versatile two or three step reaction protocols with each step having high efficiency. Structure-activity relationship studies established that analog 2i, with 6'-methoxyindole and 2,4,5-trifluorobenzyl substituents, had the greatest potency for activation of N1303K-CFTR, with EC50 ∼600 nM representing an ∼17-fold improvement over the original compound identified in a small molecule screen.
['Son|Jung-Ho|JH|', 'Phuan|Puay-Wah|PW|', 'Zhu|Jie S|JS|', 'Lipman|Elena|E|', 'Cheung|Amy|A|', 'Tsui|Ka Yi|KY|', 'Tantillo|Dean J|DJ|', 'Verkman|Alan S|AS|', 'Haggie|Peter M|PM|', 'Kurth|Mark J|MJ|']
D000627:Aminophenols D000818:Animals D002460:Cell Line D065101:Chloride Channel Agonists D003550:Cystic Fibrosis D019005:Cystic Fibrosis Transmembrane Conductance Regulator D006801:Humans D007211:Indoles D008958:Models, Molecular D009154:Mutation D010880:Piperidines D015363:Quinolones D051381:Rats D013329:Structure-Activity Relationship
CFTR Potentiator Cystic fibrosis N1303K-CFTR Modulator c.3700A>G