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Discovery of pyrrolidine-based β-secretase inhibitors: lead advancement through conformational design for maintenance of ligand binding efficiency.

Abstract：

:We have developed a novel series of pyrrolidine derived BACE-1 inhibitors. The potency of the weak initial lead structure was enhanced using library-based SAR methods. The series was then further advanced by rational design while maintaining a minimal ligand binding efficiency threshold. Ultimately, the co-crystal structure was obtained revealing that these inhibitors interacted with the enzyme in a unique fashion. In all, the potency of the series was enhanced by 4 orders of magnitude from the HTS lead with concomitant increases in physical properties needed for series advancement. The progression of these developments in a systematic fashion is described.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Stachel SJ,Steele TG,Petrocchi A,Haugabook SJ,McGaughey G,Katharine Holloway M,Allison T,Munshi S,Zuck P,Colussi D,Tugasheva K,Wolfe A,Graham SL,Vacca JP

doi

10.1016/j.bmcl.2011.11.024

subject

Has Abstract

pub_date

2012-01-01 00:00:00

pages

240-4

issue

1

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(11)01556-3

journal_volume

22

pub_type

杂志文章

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