title: Novel low molecular weight spirodiketopiperazine derivatives potently inhibit R5 HIV-1 infection through their antagonistic effects on CCR5.
abstract: Novel low molecular weight spirodiketopiperazine derivatives which potently inhibit R5 human immunodeficiency virus type 1 (HIV-1) infection through their antagonistic effects on CCR5 were identified. One such compound E913 (M(r) 484) specifically blocked the binding of macrophage inflammatory protein-1alpha (MIP-1alpha) to CCR5 (IC(50) 0.002 microm) and MIP-1alpha-elicited cellular Ca(2+) mobilization (IC(50) approximately 0.02 microm). E913 potently inhibited the replication of laboratory and primary R5 HIV-1 strains as well as various multidrug-resistant monocyte/macrophage tropic (R5) HIV-1 at IC(50) values of 0.03 to 0.06 microm. E913 was inactive against T cell tropic (X4) HIV-1; however, when combined with a CXCR4 antagonist AMD-3100, E913 potently and synergistically inhibited the replication of dualtropic HIV-1 and a 50:50 mixture of R5 and X4 HIV-1. Antagonism in anti-HIV-1 activity was not seen when E913 was combined with the reverse transcriptase inhibitor zidovudine or protease inhibitors. E913 proved to compete with the binding of antibodies to CCR5 which recognize the C-terminal half of the second extracellular loop (ECL2B) of CCR5. E913 and its analogs are acid-resistant and orally bioavailable in rodents. These data warrant that spirodiketopiperazine derivatives be further developed as potential therapeutics for HIV-1 infection.
authors.affiliation: Department of Internal Medicine II, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Maeda
authors.forename: K
authors.initials: K
authors.lastname: Yoshimura
authors.forename: S
authors.initials: S
authors.lastname: Shibayama
authors.forename: H
authors.initials: H
authors.lastname: Habashita
authors.forename: H
authors.initials: H
authors.lastname: Tada
authors.forename: K
authors.initials: K
authors.lastname: Sagawa
authors.forename: T
authors.initials: T
authors.lastname: Miyakawa
authors.forename: M
authors.initials: M
authors.lastname: Aoki
authors.forename: D
authors.initials: D
authors.lastname: Fukushima
authors.forename: H
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001596:Benzylamines; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D006224:Cricetinae; D000080027:Cyclams; D018432:Drug Resistance, Multiple; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008970:Molecular Weight; D010879:Piperazines / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D001596:Benzylamines; D065100:CCR5 Receptor Antagonists; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019402:Macrophage Inflammatory Proteins; D010879:Piperazines; D019713:Receptors, CCR5; C088327:plerixafor; D002118:Calcium