Discovery of BNC375, a Potent, Selective, and Orally Available Type I Positive Allosteric Modulator of α7 nAChRs was written by 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, Stephanie;Andriambeloson, Emile;Huyard, Bertrand;Poiraud, Etienne;Paul, Dharam;O’Connor, Susan M.. And the article was included in ACS Medicinal Chemistry Letters in 2019.Reference of 28020-37-3 This article mentions the following:
Pos. 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 stereochem. around the central cyclopropyl ring: for example, (R,R)-13 (BNC375) and its analogs with RR stereochem. around the central cyclopropyl ring are Type I PAMs, whereas compounds in the same series with SS stereochem. (e.g., (S,S)-13) are Type II PAMs as measured using patch-clamp electrophysiol. 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 mol. with good CNS-drug like properties and clin. candidate potential. In the experiment, the researchers used many compounds, for example, 3-Amino-2,6-dimethoxypyridine (cas: 28020-37-3Reference of 28020-37-3).
3-Amino-2,6-dimethoxypyridine (cas: 28020-37-3) belongs to pyridine derivatives. Pyridine’s the lone pair does not contribute to the aromatic system but importantly influences the chemical properties of pyridine, as it easily supports bond formation via an electrophilic attack. Pyridine derivatives are also useful as small-molecule α-helix mimetics that inhibit protein-protein interactions, as well as functionally selective GABA ligands.Reference of 28020-37-3