{"id":13264,"date":"2024-01-08T13:03:06","date_gmt":"2024-01-08T13:03:06","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=13264"},"modified":"2024-01-08T13:03:06","modified_gmt":"2024-01-08T13:03:06","slug":"2023-design-synthesis-and-biological-evaluation-of-a-novel-series-of-124-oxadiazole-inhibitors-of-slack-potassium-channels-identification-of-in-vitro-tool-vu0935685","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/ja\/resource_library\/2023-design-synthesis-and-biological-evaluation-of-a-novel-series-of-124-oxadiazole-inhibitors-of-slack-potassium-channels-identification-of-in-vitro-tool-vu0935685\/","title":{"rendered":"2023 &#8211; Design, synthesis, and biological evaluation of a novel series of 1,2,4-oxadiazole inhibitors of SLACK potassium channels: Identification of in vitro tool VU0935685"},"content":{"rendered":"<p>Malignant migrating\u00a0partial seizure\u00a0of infancy (MMPSI) is a devastating and pharmacoresistant form of infantile epilepsy. MMPSI has been linked to multiple gain-of-function (GOF) mutations in the\u00a0KCNT1\u00a0gene, which encodes for a\u00a0potassium channel\u00a0often referred to as\u00a0SLACK.\u00a0SLACK\u00a0channels are sodium-activated potassium channels distributed throughout the\u00a0central nervous system\u00a0(CNS) and the periphery. The investigation described here aims to discover SLACK channel inhibitor tool compounds and profile their\u00a0pharmacokinetic\u00a0and\u00a0pharmacodynamic\u00a0properties. A SLACK channel inhibitor VU0531245 (VU245) was identified via a high-throughput screen (HTS) campaign. Structure-activity relationship (SAR) studies were conducted in five distinct regions of the hit VU245. VU245 analogs were evaluated for their ability to affect SLACK channel activity using a thallium\u00a0flux assay\u00a0in HEK-293 cells stably expressing wild-type (WT) human SLACK. Selected analogs were tested for metabolic stability in mouse\u00a0liver microsomes\u00a0and plasma-protein binding in mouse plasma. The same set of analogs was tested via thallium flux for activity versus human A934T SLACK and other structurally related potassium channels, including SLICK and Maxi-K. In addition, potencies for selected VU245 analogs were obtained using whole-cell\u00a0electrophysiology\u00a0(EP) assays in\u00a0CHO cells\u00a0stably expressing WT human SLACK through an\u00a0automated patch clamp\u00a0system. Results revealed that this scaffold tolerates structural changes in some regions, with some analogs demonstrating improved SLACK inhibitory activity, good selectivity against the other channels tested, and modest improvements in\u00a0metabolic clearance. Analog VU0935685 represents a new, structurally distinct small-molecule inhibitor of SLACK channels that can serve as an\u00a0<em>in vitro<\/em>\u00a0tool for studying this target.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[50,53,76],"therapeutic_areas":[55,143],"target_categories":[61],"target_families":[],"targets":[],"resource_keyword":[],"class_list":["post-13264","resource_library","type-resource_library","status-publish","hentry","products_tags-syncropatch-384","resource_type-publication","application_areas-ion-channels","application_areas-assay-development-and-validation","application_areas-drug-discovery","therapeutic_areas-cns","therapeutic_areas-assay-development-and-validation","target_categories-voltage-gated-ion-channels"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library\/13264","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=13264"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/products_tags?post=13264"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_type?post=13264"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/application_areas?post=13264"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/therapeutic_areas?post=13264"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_categories?post=13264"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_families?post=13264"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/targets?post=13264"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_keyword?post=13264"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}