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

Eur J Med Chem. 2017 Jan 27:126:1-6. doi: 10.1016/j.ejmech.2016.10.004.

Wei-Chieh Cheng ¹, Jen-Hon Wang ², Wen-Yi Yun ³, Huang-Yi Li ³, Jia-Ming Hu ³

Affiliations

1 Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115, Taiwan; Department of Chemistry, National Cheng-Kung University, 1, University Road, Tainan 701, Taiwan. Electronic address: wcheng@gate.sinica.edu.tw.
2 Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115, Taiwan; Department of Chemistry, National Cheng-Kung University, 1, University Road, Tainan 701, Taiwan.
3 Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115, Taiwan.

PMID: 27744182 DOI: 10.1016/j.ejmech.2016.10.004

Abstract

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.

Keywords

Azasugar; Combinatorial chemistry; Fabry disease; Lysosomal α-galactosidase; Pharmacological chaperone; Polyhydroxylated pyrrolidine.

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