{"id":6306,"date":"2023-02-17T06:57:04","date_gmt":"2023-02-17T06:57:04","guid":{"rendered":"https:\/\/beta.nanion.de\/resource_library\/2019-discovery-of-bnc375-a-potent-selective-and-orally-available-type-i-positive-allosteric-modulator-of-%ce%b17-nachrs\/"},"modified":"2023-02-17T06:57:04","modified_gmt":"2023-02-17T06:57:04","slug":"2019-discovery-of-bnc375-a-potent-selective-and-orally-available-type-i-positive-allosteric-modulator-of-%ce%b17-nachrs","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/ja\/resource_library\/2019-discovery-of-bnc375-a-potent-selective-and-orally-available-type-i-positive-allosteric-modulator-of-%ce%b17-nachrs\/","title":{"rendered":"2019 &#8211; Discovery of BNC375, a Potent, Selective, and Orally Available Type I Positive Allosteric Modulator of \u03b17 nAChRs"},"content":{"rendered":"<p>Positive allosteric modulators (PAMs) of \u03b17 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\u2013kinetic 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\u2013activity optimization efforts have led to the discovery of BNC375, a small molecule with good CNS-drug like properties and clinical candidate potential.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[44],"resource_type":[75],"application_areas":[50,76],"therapeutic_areas":[55],"target_categories":[337],"target_families":[360],"targets":[189],"resource_keyword":[],"class_list":["post-6306","resource_library","type-resource_library","status-publish","hentry","products_tags-patchliner","resource_type-publication","application_areas-ion-channels","application_areas-drug-discovery","therapeutic_areas-cns","target_categories-ligand-gated-ion-channels","target_families-nicotinic-acetylcholine-receptors","targets-achr-7"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library\/6306","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/media?parent=6306"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/products_tags?post=6306"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_type?post=6306"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/application_areas?post=6306"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/therapeutic_areas?post=6306"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_categories?post=6306"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_families?post=6306"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/targets?post=6306"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_keyword?post=6306"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}