The resurgence of covalent drugs

REVIEWS

The resurgence of covalent drugs

Juswinder Singh*, Russell C.Petter*, Thomas A.Baillie and Adrian Whitty

Abstract | Covalent drugs have proved to be successful therapies for various indications, but largely owing to safety concerns, they are rarely considered when initiating a target-directed drug discovery project. There is a need to reassess this important class of drugs, and to reconcile the discordance between the historic success of covalent drugs and the reluctance of most drug discovery teams to include them in their armamentarium. This Review surveys the prevalence and pharmacological advantages of covalent drugs, discusses how potential risks and challenges may be addressed through innovative design, and presents the broad opportunities provided by targeted covalent inhibitors.

Drugs that form a covalent attachment to their target have traditionally been considered as conceptually distinct from conventional non-covalent drugs. In particular, the fact that such drugs derive part of their affinity by forming a covalent bond with their target has engendered anxiety concerning their potential for off-target reactivity and has led to these drugs being disfavoured as a drug class.These concerns largely stem from pioneering work that was carried out in the early 1970s on the hepatotoxic properties of compounds such as bromobenzene and acetaminophen, which undergo metabolism to form highly reactive intermediates that covalently bind to liver proteins.Although there has been much controversy over the years on the role of covalent binding in the pathogenesis of idiosyncratic drug-related toxicity, the formation of chemically reactive drug metabolites has been viewed as a risk factor in drug development, either through direct tissue damage or through haptenization of proteins that may elicit an immune response.

Consequently, despite many examples of successful and effective drugs that function through a covalent mechanism (for example, esomeprazole (Nexium; AstraZeneca) and clopidogrel (Plavix; Sanofi-Aventis/ Bristol-Myers Squibb); see http://www.nature.com/nrd/journal/v10/n4/suppinfo/nrd3410.html

Web End =Supplementary informa http://www.nature.com/nrd/journal/v10/n4/suppinfo/nrd3410.html

Web End =tion S1 (table)), there has been a reluctance toapply a covalent mode of action in drug discovery programmes. Indeed, essentially all existing first-in-class covalent drugs were initially discovered through screening in biological assays, and their covalent molecular mechanisms were elucidated afterwards.

In recent years, it has been recognized that the distinct strengths of covalent and non-covalent modes of drug action may be combined by designing compounds that combine carefully tuned...