title: Improving potencies and properties of CD4 down-modulating CADA analogs.
abstract: BACKGROUND
  CADA is a synthetic small molecule that inhibits HIV replication in cell cultures through down-modulating cell surface CD4 by inhibiting cotranslational translocation of nascent CD4 across the ER membrane in a signal sequence-specific manner. Analogs have been prepared mainly to increase potency and investigate the mechanism of action.
  
  
  METHODS
  This article reviews progress on discovery of more potent CADA analogs, including symmetrical and unsymmetrical compounds, as well as fluorescent derivatives. The article also discusses some properties of CADA and a more potent analog (KKD023) that are relevant to drug development, including aqueous solubility, permeability, metabolism and oral bioavailability.
  
  
  CONCLUSIONS
  Further studies on CADA analogs should focus on improving both potency and drug-like properties, and on elucidating the detailed mechanism of action. Solubility and permeability may be improved by reducing molecular weight, decreasing molecular flexibility and symmetry, or by a prodrug approach inducing active transport. Identifying the molecular mechanism of CD4 down-modulation may aid in assessing potential side effects of such immunomodulatory/anti-HIV drugs, and it could potentially lead to a general approach to designing drugs for specifically down-modulating other cell-surface proteins.
authors.affiliation: University of Nevada, Department of Chemistry, Reno, Nevada 89557-0216, USA. twb@unr.edu
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Bell
authors.forename: Violeta G
authors.initials: VG
authors.lastname: Demillo
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.forename: Kurt
authors.initials: K
authors.lastname: Vermeire
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D015704:CD4 Antigens / Q000187:drug effects* / Q000378:metabolism; D015195:Drug Design; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D010539:Permeability; D012995:Solubility; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: C498074:9-benzyl-3-methylene-1,5-di-p-toluenesulfonyl-1,5,9-triazacyclododeane; D019380:Anti-HIV Agents; D015704:CD4 Antigens; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; C575158:KKD023; D013449:Sulfonamides