| Budget Amount *help |
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2017: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
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| Outline of Final Research Achievements |
In general, fluorination increases lipophilicity because the carbon-fluorine bond is more hydrophobic than the carbon-hydrogen bond, often enhancing cell membrane penetration and oral bioavailability of the compounds. Here, we newly designed and synthesized various novel PIs and attempted to determine proper fluorination sites in various moieties consisting of certain PIs. We found that various PIs acquire more potent anti-HIV-1 activity with proper fluorination. An existing challenge in development of novel PIs is that presently clinically available PIs are metabolized by cytochrome P450 enzymes and require co-administration of CYP inhibitors, causing annoying drug-drug interactions leading to adverse effects. We found that alkylamino modification at C5-position of tetrahydropyrano-tetrahydrofuran-containing PIs potentiates activity against multi-PI-resistant HIV-1 and the stability to CYP enzymes.
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