Rapid preparation of (3R,4S,5R) polyhydroxylated pyrrolidine-based libraries to discover a pharmacological chaperone for treatment of Fabry disease

• Published in: European journal of medicinal chemistry Vol. 126; pp. 1 - 6
• Main Authors: Cheng, Wei-Chieh, Wang, Jen-Hon, Yun, Wen-Yi, Li, Huang-Yi, Hu, Jia-Ming
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 27.01.2017; Elsevier
• Subjects: alpha-Galactosidase - antagonists & inhibitors; alpha-Galactosidase - genetics; Animals; Azasugar; Cercopithecus aethiops; Chemistry, Medicinal; Combinatorial chemistry; COS Cells; Drug Design; Drug Stability; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Fabry disease; Fabry Disease - drug therapy; Humans; Hydroxylation; Kinetics; Life Sciences & Biomedicine; Lysosomal α-galactosidase; Mutation; Pharmacological chaperone; Pharmacology & Pharmacy; Polyhydroxylated pyrrolidine; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Pyrrolidines - pharmacology; Pyrrolidines - therapeutic use; Science & Technology; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Small Molecule Libraries - therapeutic use; Stereoisomerism; Temperature; Azasugar; Fabry disease; Combinatorial chemistry; Lysosomal α-galactosidase; Pharmacological chaperone; Polyhydroxylated pyrrolidine; EFFICACY; POTENT; ENZYME REPLACEMENT; INHIBITION; THERAPY; LYMPHOBLASTS; Lysosomal alpha-galactosidase; 1-DEOXYGALACTONOJIRIMYCIN; GAUCHER
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.10.004

The rapid discovery of a pharmacological chaperone toward human α-Gal A for the treatment of Fabry disease is described. Two polyhydroxylated pyrrolidines with the (3R,4S,5R) configuration pattern underwent rapid substituent diversity by conjugating the primary aminomethyl moiety of each with a variety of carboxylic acids to generate two libraries (2 × 60 members). Our bioevaluation results showed one member with the (2R,3R,4S,5R) configuration pattern and bearing a 5-cyclohexylpentanoyl group as a substituent moiety possessed sufficient chaperoning capability to rescue α-Gal A activity in the lymphocyte of the N215S Fabry patient-derived cell line and other α-Gal A mutants in COS7 cells. [Display omitted] •New pyrrolidine-based pharmacological chaperones for Fabry disease are developed.•Compound 8 is a potent and selective pharmacological chaperone for Fabry disease.•It is a durable and non-substrate competitive pharmacological chaperone.