Three Decades of P-gp Inhibitors: Skimming Through Several Generations and Scaffolds

• Type: Another Publication in an International Scientific Journal
• Date: 2012

Authors

Palmeira, A (Author) Other; Sousa, E (Author) FFUP; Vasconcelos, MH (Author) FFUP; Pinto, MM (Author) FFUP

Journal

Title: Current Medicinal Chemistry

Vol. 19

Pages: 1946-2025

ISSN: 0929-8673

Publisher: Bentham

Indexing

ISI Proceedings

ISI Web of Knowledge - 328 Citations

Scopus - 343 Citations

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: P-002-AR4

DOI: 10.2174/092986712800167392

Abstract (EN): Many tumor cells become resistant to commonly used cytotoxic drugs due to the overexpression of ATP-binding cassette (ABC) transporters, namely P-glycoprotein (P-gp). The discovery of the reversal of multidrug resistance (MDR) by verapamil occured in 1981, and in 1968 MDR Chinese hamster cell lines were isolated for the first time. Since then, P-gp inhibitors have been intensively studied as potential MDR reversers. Initially, drugs to reverse MDR were not specifically developed for inhibiting P-gp; in fact, they had other pharmacological properties, as well as a relatively low affinity for MDR transporters. An example of this first generation P-gp inhibitors is verapamil. The second generation included more specific with less side-effect inhibitors, such as dexverapamil or dexniguldipine. A third generation of P-gp inhibitors comprised compounds such as tariquidar, with high affinity to P-gp at nanomolar concentrations. These generations of inhibitors of P-gp have been examined in preclinical and clinical studies; however, these trials have largely failed to demonstrate an improvement in therapeutic efficacy. Therefore, new and innovative strategies, such as the fallback to natural products, the design of peptidomimetics and dual activity ligands emerged as a fourth generation of P-gp inhibitors. The chemistry of P-gp inhibitors, as well as their in vitro, in vivo and clinical trials are discussed, and the most recent advances concerning P-gp modulators are reviewed.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 80