4^th European Biopharma Congress

4’-C-Ethynl-2’-fluoro-2-deoxyadenosine (EFdA) has attracted much attention due to its extremely excellent anti-HIV

properties (1. prevent the emergence of resistant HIV mutants 2. over 400 times more active than AZT and several orders

of magnitude more active than the other clinical reverse-transcriptase inhibitor 2’, 3’-dideoxynucleoside drugs 3. very low toxic

4. long acting 5. could be used for prophylaxis, and so on). EFdA is now under clinical investigation as MK-8591 by Merck

& Co. In my talk, the development of EFdA, especially the design of it will　be presented and discussed. For the design of the

modified nucleoside which could solve the problems (1. emergence of drug-resistant HIV-mutants. 2. adverse effects by drugs.

3. necessary to take plenty number of drugs) that the clinical drugs have, I have proposed the following working hypotheses to

solve the problems. They are: (1) the way to prevent the emergence of resistant HIV mutants, (2) the way to decrease the toxicity

of modified nucleosides, (3) the way to provide the nucleoside with the stability to both enzymatic and acidic hydrolysis of

nucleobase. 4’-C-substituted-2’-deoxynucleoside was designed to meet the hypotheses (1), (3) and the 2-site-modification was

conducted to meet the hypothesis (2). The details of the hypotheses and the reason of the 4’-C-substitution will be discussed.

To prevent the deamination of adenine base, fluorine atom was introduced at the 2-position of adenine base. Finally, EFdA

which is modified at the two positions of the physiologic 2’-deoxyadenosine and has extremely excellent anti-HIV properties

been successfully developed.