Designing Irreversible Inhibitors—Worth the Effort?

Abstract

Despite the unquestionable success of numerous irreversible drugs that are currently in clinical use, such as acetylsalicylic acid (Aspirin) and penicillin, the number of such approved drugs is much lower than that of noncovalent drugs. Over the years, the potential off-target effects of these types of compounds have been the primary concern that has hampered their development. However, their remarkable advantages over noncovalent drugs and a better analysis of the risks have decreased the widespread skepticism surrounding them. The design of irreversible inhibitors is a challenge, particularly considering that in some cases their efficacy is due to complex and unexpected mechanisms of action. In this review the main advantages of irreversible inhibition are summarized, and the complexity of certain covalent modification mechanisms is highlighted with selected examples.

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

“…Eur.J.2020, 26,1 196 -1237 www.chemeurj.org 2019 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim ation is based on the fact that many registered drugs targeting enzymes( including those discovered more than ac entury ago and those registered in recent years) are, in fact, covalent modifiers(i.e.,they interact with their biological target through either reversible or irreversible formation of covalentb onds); hence,t he presence of ar eactive moiety in their molecule is utilized to reveal their mechanism of action. [261][262][263] As with compounds violating the Ro5, which were discussed in section 4.1, nonserendipitous discoveryo fc ovalenti nhibitors is ac hallenging task. In this case, the problem is related mainly to potential toxicityd ue to the lack of chemical selectivity in the transformations of the reactive group.…”

The Cysteinome of Protein Kinases as a Target in Drug Development

“…[2] An example of ad rug acting through an irreversible mechanism is aspirin, which specifically reacts with as erine residue on cyclooxygenases.O ther famous examples are b-lactam antibiotics like penicillins and cephalosporins,h ighly efficient antibiotics that inhibit the cross-linking of bacterial cell walls by covalently targeting DD-transpeptidase. [3] Forsome target families such as proteases,c ovalent inhibitors represent ap redominant inhibitor class. [4] Likewise,p rodrugs have been developed that act by generating areactive irreversible inhibitor in situ.…”

Guidelines for the Synthesis of Small‐Molecule Irreversible Probes Targeting G Protein‐Coupled Receptors

“…The choice of chemoreactive groups is more extensive and even more functionalities can be found when looking at literature examples targeting other proteins than GPCRs . Even though, a lot of these groups have not been frequently used in pharmacological tools targeting GPCRs they still might be considered as valuable alternative options.…”