Open AccessAhp-Cyclodepsipeptide Inhibitors of Elastase: Lyngbyastatin 7 Stability, Scalable Synthesis, and Focused Library Analysis
Author(s) -
Danmeng Luo,
Hendrik Luesch
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00473
Subject(s) - pharmacophore , elastase , serine protease , chemistry , combinatorial chemistry , potency , stereochemistry , biochemistry , protease , computational biology , enzyme , in vitro , biology
Due to the potency and selectivity of lyngbyastatin 7 in inhibiting neutrophil elastase, a serine protease involved in numerous diseases, this cyclodepsipeptide was considered as a promising lead and subjected to further developmental studies. Lyngbyastatin 7 displayed a favorable serum and microsomal stability profile. The large-scale synthesis of key building blocks was performed on gram scale with improved yields and simplified purification procedures. To tailor the complex structure, define the minimal pharmacophore, and modulate the physicochemical properties of the lead scaffold, the first pilot library of analogues was designed and synthesized for structure-activity relationship studies. We uncovered the essential role of the side chain, indicating that the minimal structural requirements for elastase inhibition extended beyond the 3-amino-6-hydroxy-2-piperidone (Ahp) and 2-aminobutenoic acid (Abu) moieties conventionally known to convey antiprotease activity and elastase selectivity, respectively. Our studies will facilitate the design and development of this class of elastase inhibitors.