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 R3

SUBMITTER: Sharma LK 

PROVIDER: S-EPMC8693618 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature