Rational design and synthesis of highly potent pharmacological chaperones for treatment of N370S mutant Gaucher disease.
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).
Wang
Guan-Nan
GN
State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical Sciences, Peking University, Xue Yuan Road No. 38, Beijing 100191, China.
Reinkensmeier
Gabriele
G
Zhang
Si-Wei
SW
Zhou
Jian
J
Zhang
Liang-Ren
LR
Zhang
Li-He
LH
Butters
Terry D
TD
Ye
Xin-Shan
XS
D015195:Drug Design; D005776:Gaucher Disease / Q000188:drug therapy* / Q000235:genetics; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D050111:Imino Sugars / Q000138:chemical synthesis* / Q000494:pharmacology; D007769:Lactams / Q000138:chemical synthesis* / Q000494:pharmacology; D020125:Mutation, Missense; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D050111:Imino Sugars; D007769:Lactams; D005962:Glucosylceramidase