Aminobenzisoxazole compounds as agonists of α7 nicotinic acetylcholine receptors: a patent evaluation (WO 2017027600)

ABSTRACT

Introduction: alpha 7 subtype nicotinic acetylcholine receptor (α7 nAChR) ligands, that is, ligands that interact with the orthosteric or allosteric binding sites of α7 nAChR, hold great potential for several therapeutic applications. Numerous compounds have been designed targeting α7 nAChR but most of them cannot be used therapeutically for various reasons.

Areas covered: The patent application describes a series of germinal substituted aminobenzisoxazole compounds as α7 nAChR ligands. These compounds were claimed as potential therapeutics for treating and/or improving cognitive function. All of the (R)-stereoisomer presented high binding activities for α7 nAChR and several compounds displayed excellent selectivity over 5-HT₃R.

Expert opinion: The privileged structure-derived modification via bioisosterism and scaffold hopping is an important approach for seeking novel α7 nAChR ligands. The claimed germinal substituted aminobenzisoxazole derivatives with low tPSA values as well as low number of hydrogen bond donors and acceptors are supposed to have sufficient BBB penetration. Although there is a lack of essential biological data and the molecular mechanisms are not clear, these compounds stand for a new type of α7 nAChR ligands and deserve further studies.

KEYWORDS:

• Nicotinic receptors
• α7 nAchR
• cognition
• agonists
• allosteric modulators

Article highlights

• There is an urgent demand for developing new α7 nAChR ligands with good pharmacokinetic property and low toxicity.

• A patent application on a series of germinal substituted aminobenzisoxazole compounds as α7 nAChR ligands is examined in this publication.

• The privileged structure-derived modification via bioisosterism and scaffold hopping is an important approach for seeking novel α7 nAChR ligands.

• The claimed germinal substituted aminobenzisoxazole derivatives with low tPSA values as well as low number of hydrogen bond donors and acceptors are supposed to have sufficient BBB penetration.

• Overall, the claimed compounds stand for a new type of α7 nAChR ligands and deserve further studies.

Declaration of interest

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

Additional information

Funding

This paper has not been funded.