title: Design, synthesis, and biological evaluation of the combinatorial library with a new spirodiketopiperazine scaffold. Discovery of novel potent and selective low-molecular-weight CCR5 antagonists.
abstract: We previously reported the discovery of several spirodiketopiperazine derivatives as potent CCR5 antagonists with anti-HIV activity. Herein, we describe in detail the identification of these lead compounds using a combinatorial chemistry approach. A novel spirodiketopiperazine scaffold was designed on the basis of the concept of the privileged structure of G-protein-coupled receptors (GPCRs). This new framework was obtained in acceptable yield with high purity from the readily prepared isonitrile resin through the Ugi reaction, sequential transformations, and cyclative cleavage. By measuring the inhibitory activity of each compound in the initial library against the intracellular calcium mobilization stimulated by MIP-1alpha, several compounds were found to show modest but selective CCR5 antagonistic activity. After the rapid evaluation of these hit compounds, several single-digit nanomolar, low-molecular-weight CCR5 antagonists that can potently block the infectivity and replication of laboratory and clinical strains of HIV as well as those of highly drug-resistant HIV variants with minimal cytotoxicity have been identified.
authors.affiliation: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd., Osaka 618-8585, Japan. habashita@ono.co.jp
authors.forename: Hiromu
authors.initials: H
authors.lastname: Habashita
authors.forename: Masaya
authors.initials: M
authors.lastname: Kokubo
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Hamano
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Hamanaka
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toda
authors.forename: Shiro
authors.initials: S
authors.lastname: Shibayama
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tada
authors.forename: Kenji
authors.initials: K
authors.lastname: Sagawa
authors.forename: Daikichi
authors.initials: D
authors.lastname: Fukushima
authors.forename: Kenji
authors.initials: K
authors.lastname: Maeda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D020650:Combinatorial Chemistry Techniques; D006224:Cricetinae; D015195:Drug Design; D024921:Drug Resistance, Multiple, Viral; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology; D008958:Models, Molecular; D008970:Molecular Weight; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000737:chemistry*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D010879:Piperazines; D019713:Receptors, CCR5; D013141:Spiro Compounds; D002118:Calcium