Details

Autor(en) / Beteiligte

• 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

Titel

Discovery of BNC375, a Potent, Selective, and Orally Available Type I Positive Allosteric Modulator of α7 nAChRs

Ist Teil von

• ACS medicinal chemistry letters, 2019-05, Vol.10 (5), p.754-760

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2019

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.