Cyclization-activated prodrugs.
Many drugs suffer from an extensive first-pass metabolism leading to drug inactivation and/or production of toxic metabolites, which makes them attractive targets for prodrug design. The classical prodrug approach, which involves enzyme-sensitive covalent linkage between the parent drug and a carrier moiety, is a well established strategy to overcome bioavailability/toxicity issues. However, the development of prodrugs that can regenerate the parent drug through non-enzymatic pathways has emerged as an alternative approach in which prodrug activation is not influenced by inter- and intraindividual variability that affects enzymatic activity. Cyclization-activated prodrugs have been capturing the attention of medicinal chemists since the middle-1980s, and reached maturity in prodrug design in the late 1990 s. Many different strategies have been exploited in recent years concerning the development of intramoleculary-activated prodrugs spanning from analgesics to anti-HIV therapeutic agents. Intramolecular pathways have also a key role in two-step prodrug activation, where an initial enzymatic cleavage step is followed by a cyclization-elimination reaction that releases the active drug. This work is a brief overview of research on cyclization-activated prodrugs from the last two decades.
Gomes
Paula
P
Centro de Investigação em Química da Universidade do Porto, Departamento de Química, Faculdade de Ciências, Universidade do Porto, Porto, Portugal. pgomes@fc.up.pt
Vale
Nuno
N
Moreira
Rui
R
D000577:Amides / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D000818:Animals; D001682:Biological Availability; D003500:Cyclization; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism
D000577:Amides; D000588:Amines; D010455:Peptides; D011355:Prodrugs