Rational design and synthesis of highly potent pharmacological chaperones for treatment of N370S mutant Gaucher disease

Guan-Nan Wang; Gabriele Reinkensmeier; Si-Wei Zhang; Jian Zhou; Liang-Ren Zhang; Li-He Zhang; Terry D Butters; Xin-Shan Ye

doi:10.1021/jm801506m

Rational design and synthesis of highly potent pharmacological chaperones for treatment of N370S mutant Gaucher disease

J Med Chem. 2009 May 28;52(10):3146-9. doi: 10.1021/jm801506m.

Authors

Guan-Nan Wang¹, Gabriele Reinkensmeier, Si-Wei Zhang, Jian Zhou, Liang-Ren Zhang, Li-He Zhang, Terry D Butters, Xin-Shan Ye

Affiliation

¹ State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical Sciences, Peking University, Xue Yuan Road No. 38, Beijing 100191, China.

PMID: 19397268
DOI: 10.1021/jm801506m

Abstract

Highly potent N-substituted delta-lactams have been rationally designed and synthesized by a concise route with a one-pot tandem reaction as key step. These iminosugars show weak inhibition of wild-type beta-glucocerebrosidase but 3- to 6-fold increases in mutant enzyme activity (N370S).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Drug Design*
Gaucher Disease / drug therapy*
Gaucher Disease / genetics
Glucosylceramidase / antagonists & inhibitors*
Glucosylceramidase / genetics
Humans
Imino Sugars / chemical synthesis*
Imino Sugars / pharmacology
Lactams / chemical synthesis*
Lactams / pharmacology
Mutation, Missense*
Structure-Activity Relationship
Substrate Specificity

Substances

Imino Sugars
Lactams
Glucosylceramidase