Prolyl oligopeptidase  (POP) is a serine endoprotease linked to neurodegenerative (e.g. Alzheimer's disease) and psychiatric (e.g. bipolar disorder) disorders. By using computational tools along with evaluation of synthetic feasibility, a first series of constrained covalent inhibitors exhibiting activity and selectivity for POP was developed. We present here the discovery of a new chemical scaffold discovered by a fully automated virtual screening.  A virtual hit molecule together with analogues were selected for synthesis and made in one to five chemical steps. Biological evaluation and metabolic stability have also been investigated. This new scaffold shows not only activity in the high nanomolar range in intacts cells but also acceptable metabolic stability. In conclusion, we described herein a scaffold with an improved profile compare to our first developed inhibitor. Investigation on the pharmacokinetic and thermodynamic profile of this scaffold is currently performed.

Virtual screening and computational optimization for the discovery of covalent prolyl oligopeptidase inhibitors with activity in human cells

244th National Meeting (2012)

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