{"doi":"10.1124/molpharm.123.000783","title":"Discovery and Characterization of VU0542270, the First Selective Inhibitor of Vascular Kir6.1/SUR2B KATP Channels","abstract":"Vascular smooth muscle K<sub>ATP</sub> channels critically regulate blood flow and blood pressure by modulating vascular tone, and therefore represent attractive drug targets for treating several cardiovascular disorders. However, the lack of potent inhibitors that can selectively inhibit Kir6.1/SUR2B (vascular K<sub>ATP</sub>) over Kir6.2/SUR1 (pancreatic K<sub>ATP</sub>) has alluded discovery despite decades of intensive research. We therefore screened 47,872 chemically diverse compounds for novel inhibitors of heterologously expressed Kir6.1/SUR2B channels. The most potent inhibitor identified in the screen was an <i>N</i>-aryl-<i>N</i>9-benzyl urea compound termed VU0542270. VU0542270 inhibits Kir6.1/SUR2B with an IC<sub>50</sub> of approximately 100 nM but has no apparent activity toward Kir6.2/SUR1 or several other members of the Kir channel family at doses up to 30 µM (&gt;300-fold selectivity). By expressing different combinations of Kir6.1 or Kir6.2 with SUR1, SUR2A, or SUR2B, the VU0542270 binding site was localized to SUR2. Initial structure-activity relationship exploration around VU0542270 revealed basic texture related to structural elements that are required for Kir6.1/SUR2B inhibition. Analysis of the pharmacokinetic properties of VU0542270 showed that it has a short in vivo half-life due to extensive metabolism. In pressure myography experiments on isolated mouse ductus arteriosus (DA) vessels, VU0542270 induced DA constriction in a dose-dependent manner similar to that of the non-specific K<sub>ATP</sub> channel inhibitor, glibenclamide. The discovery of VU0542270 provides conceptual proof that SUR2-specific K<sub>ATP</sub> channel inhibitors can be developed using a molecular target-based approach and offers hope for developing cardiovascular therapeutics targeting Kir6.1/SUR2B. <b>Significance Statement</b> Small-molecule inhibitors of vascular smooth muscle K<sub>ATP</sub> channels might represent novel therapeutics for patent ductus arteriosus, migraine headache, and sepsis, however, the lack of selective channel inhibitors has slowed progress in these therapeutic areas. Here, we describe the discovery and characterization of the first vascular-specific K<sub>ATP</sub> channel inhibitor, VU0542270.","journal":"Molecular Pharmacology","year":2024,"id":441852,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9511,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":421696,"name":"Samantha J. McClenahan","orcid":"0000-0002-1792-9700","position":1,"is_corresponding":false},{"id":896962,"name":"Changho Han","orcid":"0000-0002-0832-7070","position":2,"is_corresponding":false},{"id":1255411,"name":"Joseph D. Bungard","orcid":null,"position":3,"is_corresponding":false},{"id":1150333,"name":"Upendra Rathnayake","orcid":null,"position":4,"is_corresponding":false},{"id":344615,"name":"Olivier Boutaud","orcid":"0000-0002-8910-0598","position":5,"is_corresponding":false},{"id":298993,"name":"Joshua A. Bauer","orcid":"0000-0002-8019-900X","position":6,"is_corresponding":false},{"id":909974,"name":"Emily Days","orcid":null,"position":7,"is_corresponding":false},{"id":352918,"name":"Craig W. Lindsley","orcid":"0000-0003-0168-1445","position":8,"is_corresponding":false},{"id":235660,"name":"Elaine L. Shelton","orcid":"0000-0003-0929-2882","position":9,"is_corresponding":false},{"id":328000,"name":"Jerod S. Denton","orcid":"0000-0003-0032-8586","position":10,"is_corresponding":false},{"id":1149993,"name":"Kangjun Li","orcid":"0000-0002-7078-9444","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T02:01:11.152920Z","pmid":"38302135","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}