Small molecule CXCR4 chemokine receptor antagonists: developing drug candidates.
Chemokine receptors are a target of growing interest for new therapeutic drugs, as their role in multiple disease states has been demonstrated. The CXCR4/ CXCL12 pairing has been implicated in HIV and cancer, as well as chronic inflammatory diseases, including asthma and rheumatoid arthritis. HIV uses CXCR4 or CCR5 receptors in the key binding step of the infection process, leading to the idea that drugs could be developed to block this interaction. Cancer metastasis has also been linked to cellular communication via the chemokine pathways and hence, receptor antagonists could potentially inhibit this important pathway of disease progression. A wealth of data concerning small molecule CXCR4 receptor antagonists has been generated over the last few years, as a variety of these small molecules have been tested, and the understanding of structure activity relationships has improved. Here, we review the developing area of small molecule CXCR4 antagonists and the rapidly increasing amount of data from biological studies. Both peptidic and non-peptidic compounds have been investigated. In particular, we focus on AMD3100 and bismacrocyclic analogues, the most extensively studied class of CXCR4 antagonists, and the recent developments in this area.
Khan
Abid
A
Department of Chemistry, The University of Hull, Cottingham Road, Hull, HU6 7RX, UK.
Greenman
John
J
Archibald
Stephen J
SJ
D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001596:Benzylamines; D054377:Chemokine CXCL12 / Q000378:metabolism; D018925:Chemokines / Q000276:immunology / Q000378:metabolism; D000080027:Cyclams; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D001596:Benzylamines; D054377:Chemokine CXCL12; D018925:Chemokines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C024560:cyclam; C088327:plerixafor