{"doi":"10.1016/j.bmc.2021.116504","title":"LipE guided discovery of isopropylphenyl pyridazines as pantothenate kinase modulators","abstract":"Pantothenate kinase (PANK) is the critical regulator of intracellular levels of coenzyme A and has emerged as an attractive target for treating neurological and metabolic disorders. This report describes the optimization, synthesis, and full structure–activity relationships of a new chemical series of pantothenate competitive PANK inhibitors. Potent drug-like molecules were obtained by optimizing a high throughput screening hit, using lipophilic ligand efficiency (LipE) derived from human PANK3 IC50 values to guide ligand development. X-ray crystal structures of PANK3 with index inhibitors from the optimization were determined to rationalize the emerging structure activity relationships. The analysis revealed a key bidentate hydrogen bonding interaction between pyridazine and R306′ as a major contributor to the LipE gain observed in the optimization. A tractable series of PANK3 modulators with nanomolar potency, excellent LipE values, desirable physicochemical properties, and a well-defined structural binding mode was produced from this study.","journal":"Bioorganic & Medicinal Chemistry","year":2021,"id":195855,"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":0.9454,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":768458,"name":"Mi Kyung Yun","orcid":null,"position":1,"is_corresponding":false},{"id":767790,"name":"Chitra Subramanian","orcid":"0000-0003-1101-5307","position":2,"is_corresponding":false},{"id":738828,"name":"Rajendra Tangallapally","orcid":"0000-0002-8727-2310","position":3,"is_corresponding":false},{"id":469114,"name":"Suzanne Jackowski","orcid":"0000-0002-6855-1429","position":4,"is_corresponding":false},{"id":469113,"name":"Charles O. Rock","orcid":"0000-0001-8648-4189","position":5,"is_corresponding":false},{"id":381385,"name":"Stephen W. White","orcid":"0000-0001-8188-5944","position":6,"is_corresponding":false},{"id":360604,"name":"Richard Lee","orcid":"0000-0002-2397-0443","position":7,"is_corresponding":false},{"id":767789,"name":"Lalit Sharma","orcid":"0000-0001-9855-704X","position":0,"is_corresponding":true}],"reference_count":25,"raw_metadata":null,"created_at":"2026-07-18T23:50:11.609550Z","pmid":"34814071","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":[]}