Apr. 4, 2000 (Blacksburg, Va.) -- A research team representing public and private laboratories is developing a gel that will allow women to discreetly control their fertility and reduce the risk of infection from sexually transmitted diseases. The research was presented at the 219th American Chemical Society (ACS) National Meeting March 26-30 in San Francisco.
Virginia Tech chemistry professor Richard Gandour explains that the acylcarnitium analog, which the researchers call Z-15, has demonstrated in vitro that it is an excellent spermicide and that it inhibits HIV, yeast infection, herpes, and other sexually-transmitted diseases (STDs). "This is a product with a lot of potential that we will continue to work with to improve its activity against STDs," says Gandour.
"We want to develop an all-in-one product," says Prashant Savle. As a research scientist at Virginia Tech, he synthesized a series of analogues, including Z-15, from the natural chemical, (R)-carnitine.
"Dr. Salve devised an all synthetic route and executed it quickly and brilliantly, making this effective, affordable product possible," says Gandour. As a gel, the product could be used to coat vaginal contraceptive devices, such as diaphragm, cervical cap, sponge, and condoms, "but the goal is to develop a product for topical application for use by women who are in circumstances or cultures where they can't insist upon or do not have access to other forms of birth control or prevention against STDs," says Gustavo F. Doncel, who has been in charge of the biological characterization of this promising agent. He is head of the Sperm Biology and Contraceptive Research Laboratory of the Contraceptive Research and Development (CONRAD) Program at the Eastern Virginia Medical School. The research has been sponsored by CONRAD (http://www.conrad.org). The program, under a cooperative agreement with the U.S. Agency for International Development (USAID), has as its primary objective the development of new or improved contraceptive methods that are safe, effective, acceptable, and suitable for use in the United States and developing countries.
The gel also recently passed an FDA-recommended test as virtually nonirritating -- not a surprise to the researchers since the chemical structure is a betaine surfactant, similar to that found in baby shampoo, Gandour explains.
"In addition to being effective and nonirritating, it is important that the product be easy to use and affordable," says Savle. He explains that the incidents of HIV infection are declining in the United States while they are on the rise in the third world, particularly in India and sub-Saharan Africa. "The idea is to make a product that would be cheap enough for the USAID to be able to purchase for free distribution, so that the women in those countries would have a choice."
Professor Gandour became aware of carnitine, a muscle chemical, a decade ago when he was doing research to develop medicines for non-insulin dependent diabetes. "We made this analogue and, from its chemical structure, knew it could be a spermicide," but it was expensive and tedious to prepare from the natural product, (R)-carnitine. "Dr. Savle designed and executed the brilliant synthesis from inexpensive, synthetic compounds and asked Dr. Doncel to test this compounds," says Gandour. After initial success in in-vitro studies, "it became apparent that multi-gram quantities of starting material would be required. Savle took on the challenge of making this starting material reliably to allow synthesis of a series of Z-15 analogs. He developed a procedure that allowed us to make all forms of Z-15.
"That is important, since the FDA requires that all forms of a potential therapeutic agent be tested," explains Savle (a rule passed after the 19601s incident relating to the use of Thalidomide that resulted in birth defects). The researchers are now working to produce Z-15 in kilogram quantities for final preclinical assessment and phase one clinical trials. A patent is pending on the product.
"Drs. Doncel and Stephen D. Bryant of Buckman Laboratory International of Memphis, Tenn., contributed substantially to the success of this research," says Gandour.
The Buckman Lab specializes in industrial microorganism control. "We don't produce human medicines or products, but we do screen many compounds," explains Bryant. "We screened compounds provided by Dr. Gandour1s group for microbial activity, specifically against Candida (yeast infections)." The lab is also looking for industrial applications for Z-15 and the other compounds provided by the Virginia Tech researchers, he said.
Co-authors on the ACS paper are Savle, now Chiral Product Specialist at Aldrich in Milwaukee, Gandour, Doncel, and Bryant. The ACS paper (MEDI paper 127) is about multi-gram synthesis of Z-15. It was presented Sunday evening, March 26 as part of the Division of Medicinal Chemistry poster session.
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