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Abstract

Abstract: DESCRIPTION (provided by applicant): 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

Institution:	PARADIGM PHARMACEUTICALS, LLC
	2685 PATTON RD
	ST. PAUL, MN 55113
Fiscal Year:	2002
Department:
Project Start:	01-AUG-2002
Project End:	31-JAN-2003
ICD:	NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
IRG:	ZRG1