2-Heteroarylethylamines in medicinal chemistry: a review of 2-phenethylamine satellite chemical space

• Published in: Beilstein journal of organic chemistry Vol. 20; no. 1; pp. 1880 - 1893
• Main Authors: Nieto, Carlos, Manchado, Alejandro, García-González, Ángel, Díez, David, Garrido, Narciso M
• Format: Journal Article
• Language: English
• Published: Germany Beilstein-Institut 02.08.2024
• Subjects: 2-heteroarylethylamines; 2-phenethylamine; bioisosteres; Chemistry; medicinal chemistry; Review; scaffold hopping; 2-heteroarylethylamines; bioisosteres; scaffold hopping; 2-phenethylamine; medicinal chemistry
• ISSN: 1860-5397; 1860-5397
• DOI: 10.3762/bjoc.20.163

The concept of bioisostere replacement is of paramount importance in medicinal chemistry, as it can be employed as a rational to expand bioactive chemical space to tackle lead optimization issues like lack of potency, efficacy, and selectivity or pharmacokinetic/dynamic issues. One of the most important building blocks (in the sense of participating in a vast area of chemical space of biological importance) in medicinal chemistry is the 2-phenethyl moiety, a key component of diverse drug-like entities. Although the core 2-phenethylamine structure has been recognized by the drug discovery community, little attention has been given to the various ring-based rescaffolding procedures that can be conducted with this unit. In this regard, a review on the use of 2-heteroarylethylamines displaying pharmacological activity is reported. A detailed description of flexible, amine-opened motifs is provided, that describes therapeutic targets and other potent bioactive examples, which will be a valuable repository of phenyl, heteroaryl, and other replacement units of high value to the drug discovery community.