Identification, Structure–Activity Relationship, and Biological Characterization of 2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indoles as a Novel Class of CFTR Potentiators

Abstract

Cystic fibrosis (CF) is a life-threatening autosomal recessive disease, caused by mutations in the CF transmembrane conductance regulator (CFTR) chloride channel. CFTR modulators have been reported to address the basic defects associated with CF-causing mutations, partially restoring the CFTR function in terms of protein processing and/or channel gating. Small-molecule compounds, called potentiators, are known to ameliorate the gating defect. In this study, we describe the identification of the 2,3,4,5tetrahydro-1H-pyrido[4,3-b]indole core as a novel chemotype of potentiators. In-depth structure−activity relationship studies led to the discovery of enantiomerically pure 39 endowed with a good efficacy in rescuing the gating defect of F508del-and G551D-CFTR and a promising in vitro druglike profile. The in vivo characterization of γ-carboline 39 showed considerable exposure levels and good oral bioavailability, with detectable distribution to the lungs after oral administration to rats. Overall, these findings may represent an encouraging starting point to further expand this chemical class, adding a new chemotype to the existing classes of CFTR potentiators.

Pharmacological potentiators of the calcium signaling cascade identified by high-throughput screening

“…We screened a chemical library of 11,300 compounds, generated at the Italian Institute of Technology, and having maximal structural diversity and good drug-like properties. This library was previously used to find CFTR correctors and potentiators ( 14 , 15 ). All compounds were tested at 10 µM by addition in the microplate 20 min before the assay.…”

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

“… 97 , 98 Compounds containing a 2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indole core were able to efficiently rescue the function of F508del- and G551D-CFTR. 99 A spiro[piperidine-4,1-pyrido[3,4-b]indole compound demonstrated potentiation activity for N1303K and I1234-R1239del CFTR with additive effects when in combination with VX-770. 100 ASP-11 is an arylsulfonamide-pyrrolopyridine co-potentiator that acts synergistically with VX-770 in the rescue of F508del-, G551D-, N1303K- and W1282X-CFTR mutations in cell lines.…”

One-step synthesis of azepino[3,4-b]indoles by cooperative aza-[4 + 3] cycloaddition from readily available feedstocks

“…Based on the concept of ring fusion, azepinoindoles feature a fused-ring system comprising privileged azepine and indole moieties, thus offering not only non-aromatic and non-planar characteristics but also muti-bonding points and a specific spatial architecture for drug design. 2 a ,3 As a special subtype of this family, azepino[3,4- b ]indoles and their analogues exhibit pharmacological properties including potent inhibition of cyclin-dependent kinases (CDKs) 4 and promising antitumoral activity. 5 Accordingly, it is a highly desired scaffold that is actively pursued by synthetic chemists.…”