1557241-10-7Relevant articles and documents
Discovery of BNC375, a Potent, Selective, and Orally Available Type i Positive Allosteric Modulator of α7 nAChRs
Harvey, Andrew J.,Avery, Thomas D.,Schaeffer, Laurent,Joseph, Christophe,Huff, Belinda C.,Singh, Rajinder,Morice, Christophe,Giethlen, Bruno,Grishin, Anton A.,Coles, Carolyn J.,Kolesik, Peter,Wagner, Stéphanie,Andriambeloson, Emile,Huyard, Bertrand,Poiraud, Etienne,Paul, Dharam,O'Connor, Susan M.
, p. 754 - 760 (2019/04/17)
Positive allosteric modulators (PAMs) of α7 nAChRs can have different properties with respect to their effects on channel kinetics. Type I PAMs amplify peak channel response to acetylcholine but do not appear to influence channel desensitization kinetics, whereas Type II PAMs both increase channel response and delay receptor desensitization. Both Type I and Type II PAMs are reported in literature, but there are limited reports describing their structure-kinetic profile relationships. Here, we report a novel class of compounds with either Type I or Type II behavior that can be tuned by the relative stereochemistry around the central cyclopropyl ring: for example, (R,R)-13 (BNC375) and its analogues with RR stereochemistry around the central cyclopropyl ring are Type I PAMs, whereas compounds in the same series with SS stereochemistry (e.g., (S,S)-13) are Type II PAMs as measured using patch-clamp electrophysiology. Further fine control over the kinetics has been achieved by changing the substitutions on the aniline ring: generally the substitution of aniline with strong electron withdrawing groups reduces the Type II character of these compounds. Our structure-activity optimization efforts have led to the discovery of BNC375, a small molecule with good CNS-drug like properties and clinical candidate potential.
