title: A novel vaginal microbicide containing the rationally designed anti-HIV compound HI-443 (N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)] thiourea]).
abstract: BACKGROUND
  A focal point in contemporary research aimed at preventing the heterosexual spread of AIDS has been the development of intravaginal anti-HIV microbicides to curb the mucosal human immunodeficiency virus type 1 (HIV-1) transmission.
  
  
  METHODS
  This article reviews the preclinical activity and safety profile of the thiophene thiourea PETT derivative, HI-443 (N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)] thiourea]). HI-443 is a rationally designed non-nucleoside reverse transcriptase inhibitor (NNRTI) with unprecedented activity against primary clinical HIV-1 isolates with NRTI or NNRTI resistance, multidrug resistance as well as non-B envelope subtypes of HIV-1. HI-443 exhibited a favorable toxicity and pharmacokinetics profile following oral, intraperitoneal or intravenous administration in rodents and a favorable safety profile after repeated intravaginal dosing via a gel formulation in rabbits and pigs. HI-443 did not induce the secretion of pro-inflammatory cytokines and chemokines by three-dimensional reconstituted human vaginal epithelia integrating Langerhans cells ex vivo or in the in vivo porcine model at therapeutic dose levels. Intravaginally administered HI-443 prevented vaginal transmission of a drug-resistant clinical HIV-1 isolate in the surrogate Hu-PBL-SCID mouse model of AIDS.
  
  
  CONCLUSIONS
  The discovery of HI-443 as a non-spermicidal broad-spectrum antiretroviral agent represents a significant step forward in the development of a prophylactic microbicide without contraceptive activity for curbing heterosexual HIV transmission.
authors.affiliation: Microbicide Development Laboratory, Developmental Therapeutics Program, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, CA, USA. odcruz@chla.usc.edu
authors.forename: Osmond J
authors.initials: OJ
authors.lastname: D'Cruz
authors.forename: Sanjive
authors.initials: S
authors.lastname: Qazi
authors.forename: Seang
authors.initials: S
authors.lastname: Yiv
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015195:Drug Design; D024921:Drug Resistance, Multiple, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000635:transmission / Q000821:virology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D051379:Mice; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011817:Rabbits; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D013552:Swine; D013890:Thiourea / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; C403248:HI 443; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D013890:Thiourea