Objective: The main goal of this work is the regulatory chemical, pharmaceutical and toxicological development of S14, a new therapeutic class for the potential treatment of Parkinson’s disease (PD).

Background: The need of disease-modifiying drugs for Parkinson’s disease treatment lead us to discover S14, a selective PDE7 inhibitor, able to protect dopaminergic cell death both in cell cultures and in animal models. Moreover, we have also described that this compound is able to activate neurogenesis after 6-OHDA insult, opening a great expectation as possible therapy in PD patients. With the aim to obtain the approval of authorities for starting clinical trials in humans, an appropriate regulatory preclinical development has been carried out enabling Phase I clinical trial.

Methods: Different organic convergent synthetic methodologies have been applied to finally define an efficient pathway to obtain S14. Standard methodologies have been used to develop an oral form to administrate S14 to PD patients. S14 safety profile has been evaluated according to ICHM3: rats and dogs have been used to define the NOAEL from the dose repeated toxicology studies and standard safety pharmacology and in vitro genotoxicity studies have been also performed.

Results: S14 is easily obtained in batches of 3 Kg in a two-step synthetic procedure. The compound is stable under normal and accelerated humidity and temperature conditions (up to 18 months). The first pharmaceutical form finally developed is an oral pill of 800 mg (active substance + excipients). S14 has shown to be safe and well tolerated in cardiovascular, respiratory and central nervous systems as well as it showed negative results in the genotoxicity studies. The NOAEL from dose repeated studies (28 days) for both species, rats and dogs, has been established at 1000 mg/Kg, which indicates a wide therapeutic window (with an effective dose of 10 mg/Kg) for further treatment analyses.

Conclusions: The quinazoline derivative S14, a new PDE7 inhibitor, is ready to start clinical trials of Phase I in humans. If in those trials, proper safety and tolerability are found after S14 administration, an ulterior pilot Phase II study will be designed in a reduced number of PD patients.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/targeting-pde7-by-the-small-molecule-s14-a-potential-disease-modifying-parkinson%ef%bf%bds-disease-therapy-ready-to-start-clinical-trials/