Rational Design and Synthesis of Highly Potent Pharmacological Chaperones for Treatment of N370S Mutant Gaucher Disease

Highly potent N-substituted δ-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 β-glucocerebrosidase but 3- to 6-fold increases in mutant enzyme activity (N370S).

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Bibliographische Detailangaben
Veröffentlicht in:	Journal of medicinal chemistry 2009-05, Vol.52 (10), p.3146-3149
Hauptverfasser:	Wang, Guan-Nan, Reinkensmeier, Gabriele, Zhang, Si-Wei, Zhou, Jian, Zhang, Liang-Ren, Zhang, Li-He, Butters, Terry D, Ye, Xin-Shan
Format:	Artikel
Sprache:	eng
Schlagworte:	Biological and medical sciences 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 Medical sciences Miscellaneous Mutation, Missense Pharmacology. Drug treatments Structure-Activity Relationship Substrate Specificity
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Beschreibung
Zusammenfassung:	Highly potent N-substituted δ-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 β-glucocerebrosidase but 3- to 6-fold increases in mutant enzyme activity (N370S).
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm801506m