Computer-aided design, synthesis, and biological evaluation of [4.3.0] bicyclic prolyl oligopeptidase and fibroblast activation protein-α dual inhibitors

30 August 2021, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


We have previously described several different chemical series of bicyclic prolyl oligopeptidase (POP) inhibitors as probes for neurodegenerative diseases that demonstrated nanomolar activity in vitro and submicromolar activity in cellulo. The more recent implication of POP in cancer, together with homologous fibroblast activation protein α (FAP), implicated in tumor growth, led us to consider developing POP/FAP dual inhibitors as a promising strategy for the development of cancer therapeutics. We report herein docking-guided design of a new bicyclic scaffold and synthesis of both covalent and non-covalent bicyclic inhibitors. Biological evaluation of first-of-their-kind [4.3.0] bicyclic compounds confirmed that reactive groups, or covalent warheads, are required for inhibitor activity. This work ultimately led to a dual inhibitor equipotent to the only anti-POP/FAP drug that ever-reached clinical trials.


dual inhibition
boronic esters
covalent inhibition
Parkinson’s disease
computer-aided drug design

Supplementary materials

Supporting information
Dose response curves and NMR data


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