Bicyclic bis-heteroaryl derivatives as inhibitors of the α-synuclein protein: a patent evaluation of WO2018138088A1

ABSTRACT

Introduction: Neurodegenerative diseases commonly present misfolding and aggregation of one or more proteins, including α-synuclein, β-amyloid, and tau. Several research efforts have been made to develop therapeutic agents able to reduce the neurotoxic effects of aggregated proteins. Among these, inhibition of α-synuclein by small molecules has been considered as a promising approach.

Areas covered: Bis-heteroaryl derivatives based on the N‐[1‐(1H‐indol‐3‐yl)hexan‐2‐yl]‐1,3‐thiazole‐5‐carboxamide scaffold with different heterocyclic substitutions at the 2-thiazole position showed interesting ability to inhibit self-aggregation of α-synuclein in vitro and were claimed as potential therapeutics for various neurodegenerative diseases. The potential of the presented compounds is evaluated with respect to other similar small molecule modulators of protein aggregation reported in the patent literature.

Expert opinion: The compounds presented with ability to inhibit aggregation of α-synuclein in vitro in the low micromolar range. The biggest drawback of the presented application is the absence of pharmacokinetic, toxicity, and in vivo efficacy data. On the other hand, the number of applications in this area by UCB Biopharma SPRL (four published in last 2 years) and promising pharmacokinetic and in vivo data disclosed in a previous patent on similar molecules, indicate that these compounds may hold value as therapeutic agents for neurodegenerative disorders.

KEYWORDS:

• Bis-heteroaryl derivatives
• indole
• thiazole
• α-synuclein inhibition
• protein aggregation

Article highlights

• α-Synuclein aggregation plays a central role in the initiation and/or progression of Parkinson’s Disease and related neurodegenerative disorders.

• Inhibition of the α-synuclein protein may limit release and/or propagation and therefore reduce the neurotoxic effects of aggregated proteins.

• New bis-heteroaryl derivatives was able to inhibit self-aggregation of α–synuclein in vitro.

• The biggest drawback of the presented application is the absence of pharmacokinetic, toxicity and in vivo efficacy data.

• These compounds can be considered as promising agents for further development as they showed significant in vitro α–synuclein inhibitory activities.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.