Heteroaromatic Inhibitors of the Astacin Proteinases Meprin α, Meprin β and Ovastacin Discovered by a Scaffold-Hopping Approach.
Abstract Astacin metalloproteinases, in particular meprins α and β, as well as ovastacin, are emerging drug targets. Drug‐discovery efforts have led to the development of the first potent and selective inhibitors in the last few years. However, the most recent compounds are based on a highly flexible tertiary amine scaffold that could cause metabolic liabilities or decreased potency due to the entropic penalty upon binding to the target. Thus, the aim of this study was to discover novel conformationally constrained scaffolds as starting points for further inhibitor optimization. Shifting from flexible tertiary amines to rigid heteroaromatic cores resulted in a boost in inhibitory activity. …
Primary Evaluation of Potential Small Molecule Inhibitors of the Astacin Metalloproteinase Ovastacin, A Novel Drug Target in Female Infertility Treatment
<p>Despite huge progress in hormonal therapy and improved in vitro fertilization methods, the success rates in infertility treatment are still limited. A recently discovered mechanism revealed the interplay between the plasma protein fetuin-B and the cortical granule-based proteinase ovastacin as novel key-mechanism in the regulation of fertilization. Upon sperm-egg fusion, cleavage of a distinct zona pellucida component by ovastacin destroys the sperm receptor, enhances zona robustness and eventually provides a definitive block against polyspermy. An untimely onset of this zona hardening prior to fertilization would consequently result in infertility. Physiologically, this process is…
A Primary Evaluation of Potential Small-Molecule Inhibitors of the Astacin Metalloproteinase Ovastacin, a Novel Drug Target in Female Infertility Treatment.
Abstract Despite huge progress in hormonal therapy and improved in vitro fertilization methods, the success rates in infertility treatment are still limited. A recently discovered mechanism revealed the interplay between the plasma protein fetuin‐B and the cortical granule‐based proteinase ovastacin to be a novel key mechanism in the regulation of fertilization. Upon sperm–egg fusion, cleavage of a distinct zona pellucida component by ovastacin destroys the sperm receptor, enhances zona robustness, and eventually provides a definitive block against polyspermy. An untimely onset of this zona hardening prior to fertilization would consequently result in infertility. Physiologically, this proc…