SBIR-STTR Award

The current pandemic of sexually transmitted HIV/AIDS has created an urgent need for a new type of microbicide: one that is both a spermicide and a virucide. In a systematic effort to identify a non-detergent-type antiviral spermicide, we have synthesized a series of novel aryl phosphate derivatives of bromo-methoxy cidovudine [ZDV ] by phosphorochloridate chemistry and examined for dual-function anti-HIV and spermicidal xtivities. Unlike ZDV, our lead compound WHI-07, [5-bromo-6-methoxy-5,6-dihydro-3 '-azidothymidine- 5'-(p-bromophenyZ}- methoxy alaninyl phosphate], exhibited potent anti-WIV as well as spermicidal activities. WHI-07 was rationalIy designed to bypass the thymidine kinase-dependency of ZDV activation in genital tract leukocytes. The concentration of WHI-07, required for its anti-HIV activity was 439-fold lower than that of nonoxynol-9 EN-91. The spermicidal activity of WHI-07 was 14-fold more potent than that of N-9 and it was not associated with cytotoxicity to female genital tract epithelial cells. Preclinical studies of WHI-07 given systemically or intravaginally , lacked inflammatory and toxic effects in mice, rabbits, and cynomolgus monkeys and was nongenotoxic in in vitro and in vivo mutagenicity and carcinogenicity tests. We hypothesize that WHI-07, because of its potent anti-HIV activity, spermicidal efficacy, and lack of inflammatory and toxic effects, may be useful as a dual-function vaginalkectal microbicide for women who are at high risk of acquiring HIV/AIDS by sexual transmission. The goal of this Phase I proposal is to test: (i) the ability of WHI-07 gel formulation to prevent vaginal transmission of feline immunodeficiency virus in domestic cats as a model for sexual transmission of HIV; and (ii) to determine the developmental toxicity of WHI-07 gel formulation in the rabbit model, The successful accomplishment of these goals may provide the basis for a new strategy to prevent the sexual transmission of HIV while providing fertility control for women. Following successful completion of the Phase I in vivo efficacy and safety studies, gel formulations of WHI-07 will be further explored as a vaginal dual-function microbicide in Phase II.

Thesaurus Terms:
antiAIDS agent, antiinfective agent, drug adverse effect, drug design /synthesis /production, drug screening /evaluation, feline immunodeficiency virus sexually transmitted disease, vagina cat, female, laboratory rabbit

The current pandemic of sexually transmitted HIV/AIDS has created an urgent need for a new type of microbicide: one that is both a spermicide and a virucide. The goal of the proposed Phase II work is to further develop WHI-07, a novel 5-bromo 6-methoxy aryl phosphoramidate derivative of 3'-azido-3'-deoxythymidine (zidovudine, ZDV/AZT) as a dual-function anti-HlV microbicide. WHI-07 was rationally designed to bypass the thymidine kinase dependency of ZDV activation in genital tract secretions. WHI-07 was formulated via a nontoxic gel-microemulsion for intravaginal use as a potential candidate anti-HIV spermicide. The in vivo efficacy as well as safety studies of WHI-07 have included: (i) vaginal as well as rectal microbicide efficacy studies in the feline immunodeficiency vires (FIV)/domestic cat model for AIDS; (ii) in vivo retention of anti-HIV activity in the nonhuman primate; (iii) vaginal contraceptive efficacy studies in rabbits; (iv) single- and/or multiple-dose toxicity studies in mice, rabbits, cats as well as monkey; (v) mucosal, reproductive, and developmental toxicity studies in mice and rabbits; (vi) cytotoxicity, mutagenicity, and genotoxicy tests using human and yeast cells; and (vii) long-term carcinogenicity studies in mice. Under Phase I proposal we tested: (i) the ability of WHI-07 to prevent transvaginal as well as transrectal transmission of FIV in domestic cats as a model for sexual transmission of HIV; and (ii) determined the lack of developmental toxicity of WHI-07 in the rabbit model. Our discovery that WHI-07 either alone or in combination with a bis(cyclopentadienyl) vanadium(IV) complex, vanadocene dithiocarbamate (VDDTC), effectively protected domestic cats from systemic FIV infection via genital exposure to mucosally transmissible FIV-infected feline T cells has clinical potential for the development of a dual-function anti-HIV microbicide for sexually active women. Under Phase II funding, we propose to test the in vivo antiretroviral and contraceptive efficacies as well as safety studies of WHI-07 plus VDDTC gel-microemulsion to further explore the utility of WHI-07 either alone and in combination with VDDTC as a vaginal spermicidal anti-HIV microbicide in the clinical setting. We hypothesize that the combination of these two active agents with different mechanisms of action will potentially improve efficacy and duration of dual-protection when compared to WHI-07 alone while maintaining an adequate safety profile. The goals of Phase II study are (i) to examine the optimum microbicide activity of WHI-07 plus VDDTC gel-microemulsion versus WHI-07 alone to prevent systemic FIV infection of domestic cats from transvaginal and transrectal challenge with FIV-infected cells; (ii) to evaluate the in vivo contraceptive efficacy of WHI-07 plus VDDTC gel-microemulsion in rabbits; (iii) to assess the mucosal safety and developmental toxicity of WHI-07 plus VDDTC gel-microemulsion in rabbits; and (iv) to assess the stability WHI-07 plus VDDTC in-gel-microemulsion. The proposed Phase II work will complement and enhance the discovery and preclinical development of safe and effective dual-function microbicides at Paradigm Pharmaceuticals that may provide the basis for a new strategy to prevent the sexual transmission of HIV while providing effective fertility control for women.

Thesaurus Terms:
antiAIDS agent, antiviral agent, drug design /synthesis /production, drug screening /evaluation, feline immunodeficiency virus, spermicide communicable disease control, dosage, drug adverse effect, emulsion, family planning, gel, pharmacokinetics, pharmacology, rectum /anus, sexually transmitted disease, vagina, vanadium, zidovudine cat, female, laboratory rabbit