Applications of fluorine to the construction of bioisosteric elements for the purposes of novel drug discovery

ABSTRACT

Introduction There continues to be an exponential rise in the number of small molecule drugs that contain either a fluorine atom or a fluorinated fragment. While the unique properties of fluorine enable the precise modulation of a molecule’s physicochemical properties, strategic bioisosteric replacement of fragments with fluorinated moieties represents an area of significant growth.

Areas covered This review discusses the strategic employment of fluorine substitution in the design and development of bioisosteres in medicinal chemistry. In addition, the classic exploitation of trifluoroethylamine group as an amide bioisostere is discussed. In each of the case studies presented, emphasis is placed on the context-dependent influence of the fluorinated fragment on the overall properties/binding of the compound of interest.

Expert opinion Whereas utilization of bioisosteric replacements to modify molecular structures is commonplace within drug discovery, the overarching lesson to be learned is that the chances of success with this strategy significantly increase as the knowledge of the structure/environment of the biological target grows. Coupled to this, breakthroughs and learnings achieved using bioisosteres within a specific program are context-based, and though may be helpful in guiding future intuition, will not necessarily be directly translated to future programs. Another important point is to bear in mind what implications a structural change based on a bioisosteric replacement will have on the candidate molecule. Finally, the development of new methods and reagents for the controlled regioselective introduction of fluorine and fluorinated moieties into biologically relevant compounds particularly in drug discovery remains a contemporary challenge in organic chemistry.

KEYWORDS:

• Bioisosteres
• fluorine
• difluoromethyl
• trifluoromethyl
• trifluoroethylamine
• trifluoromethoxy
• 1,2-difluoroethylene
• amide
• conformation
• lipophilicity
• pK_a modulation
• metabolism
• hERG inhibitor
• structure-based drug design
• catalysis
• drug discovery
• SAR

Article highlights

• The versatility of fluorine and its unique properties in modern drug discovery are highlighted.

• For over a half a century, the use of bioisosteric replacements as an important strategy for molecular modification has been recognized with fluorine playing a pivotal development in this context.

• The success of bioisosteric replacements is critically dependent on not only the molecular series under evaluation but the biological target of interest.

• Early examples of bioisosterism involved replacing hydrogen with a fluorine, which demonstrated the potential benefits with changes in metabolic stability, lipophilicity, and basicity.

• The versatility of fluorinated fragments is showcased by examples utilizing the CF₂H group employed as either a OH, SH, or CH₃ bioisostere and possessed unique hydrogen bonding capabilities.

• Synthetic enablement allows facile incorporation of the vicinal 1,2-difluoroethylene motif providing a balance of lipophilicity and size with the added consideration of chirality.

• Hydrolytic stability of amide bonds makes identification of potential bioisosteres an important consideration with the use of trifluoroethylamines (H-bond donor with reduced basicity) studied for this purpose.

This box summarizes key points contained in the article.

Declaration of interest

P Richardson is a full-time employee of Pfizer Inc. He has 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 manuscript has not been funded.