Recent in vivo advances of spirocyclic scaffolds for drug discovery

ABSTRACT

Introduction

Spirocyclic scaffolds are an exceptional tool in drug design, allowing fine-tuning of a molecule’s conformational and physicochemical properties. As it expands and diversifies, so does the number of therapeutics that contain this core. Several spirocyclic drugs are already marketed, and considerably more have shown promising results.

Areas Covered

This review addresses recent in vivo studies (2017–2021) on applying spirocyclic compounds to treat various diseases, mainly grouped within neurological, infectious, and metabolic diseases and cancer. An emphasis is given on the influence of the spiro-structure on activity and consequent structure-activity study. In vivo results and their significance in the future progression towards clinical trials are also presented.

Expert opinion

Spirocyclic compounds present an exciting opportunity as an unexplored chemical space in medicinal chemistry. However, their development is hindered by their complexity and synthesis challenges. Furthermore, a clear preference is still seen for readily available spirocyclic compounds involving amine or amide bonds. Nevertheless, these are temporary as high-throughput synthesis, and computational techniques allow fast optimization studies. In our opinion, the field of spirocyclic chemistry will continue to thrive and contribute to drug development, improving activity and selectivity on emergent ailments, such as cancer, metabolic, infectious, and neurological diseases.

KEYWORDS:

• Spirocyclic
• in vivo
• structure–activity relationship
• drug design

Article highlights

• A spirocyclic compound is a set of two fused rings that share a single atom,

• They are common in medicinal chemistry, with clear benefits in increased activity (through restricted conformation) and improved pharmacokinetics.

• In recent years, several spirocyclic compounds underwent in vivo studies with good results.

• There is clear evidence of the high use of spirocyclic compounds in cancer, neurological, metabolic, and infectious diseases.

• Spirocyclic compounds’ popularity in drug research will continue to increase as their synthesis becomes more streamlined and efficient.

This box summarizes key points contained in the article.

Declaration of Interest

The authors have no other 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This research was funded by the Foundation for Science and Technology (FCT) (an organization within the Ministry of Science, Technology and Higher Education in Portugal) and the European Regional Development Fund (FEDER) through project LAQV-REQUIMTE (UIDB/50006/2020) and the University of Aveiro. Furthermore, VF Batista is supported by the FCT through a PhD grant (PD/BD/135099/2017).