抗真菌性天然物をリ࡯ドとする創薬研究- Micafungin (FK463)の創製

᛫⌀⩶ᕈᄤὼ‛ࠍ࡝࡯࠼ߣߔࠆഃ⮎⎇ⓥ- Micafungin (FK463)ߩഃ⵾Drug Discovery Using Novel Antifungal Natural Products as Lead Compounds
- Discovery of Micafungin (FK463) ᄢᧁ ⑲ᓼ‫ޔ‬౷ፉ ᣽♿‫ޔ‬㜞᧖ ኼ‫ ’ޔ‬సਯ*‫ޔ‬ᳰ↰ ᢥᤘ*
⮮ᴛ⮎ຠᎿᬺᩣᑼળ␠ ൻቇ⎇ⓥᚲ‫⮎*ޔ‬ℂ⎇ⓥᚲ
Hidenori Ohki, Masaki Tomishima, Hisashi Takasugi, Katsuyuki Maki*, Fumiaki Ikeda*
Medicinal Chemistry Research Laboratories, *Medicinal Biology Research Laboratories
Fujisawa Pharmaceutical Co., Ltd.
1980 ᐕઍએ㒠‫ޔ‬᛫↢‛⾰‫ޔ‬᛫≸‛⾰ߥߤߩൻቇ≮ᴺ೷‫∉఺ޔ‬ᛥ೙೷ߩᛩਈ߿‫ޔ‬AIDS ᗵᨴߦࠃࠆ
ᤃᗵᨴᕈᖚ⠪ߩჇടߦࠃࠅ‫ޔ‬㊀◊ߥᷓ࿷ᕈ⌀⩶∝߇Ⴧട௑ะߦ޽ࠆ‫ࠄࠇߎޕ‬ᷓ࿷ᕈ⌀⩶∝ᴦ≮⮎ߩ
㐿⊒ߪ‫߇⩶⌀ޔ‬ኋਥߢ޽ࠆࡅ࠻ߣห᭽ߦ⌀ᩭ↢‛ߦዻߔࠆߚ߼ㆬᛯᲥᕈ߇ᦼᓙߢ߈ߕ‫ޔ‬᛫⩶೷ߦᲧ
ߴߡ⪺ߒߊ┙ߜᓟࠇߡ޿ࠆ‫⃻߼ߚߩߘޕ‬࿷࿖ౝߢ૶↪ߐࠇߡ޿ࠆᷓ࿷ᕈ⌀⩶∝ߩᴦ≮⮎ߪ‫ࠛ࡝ࡐޔ‬
ࡦ♽ߩ Amphotericin B‫ ߩ♽࡞࡯࠱ࠕޔ‬Fluconazole ߥߤ 5 ⮎೷߇޽ࠆߦㆊ߉ߥ޿‫ࠇߕ޿߽߆ߒޕ‬
ߩ⮎೷߽᦭ലᕈ߿቟ోᕈߩὐߢ໧㗴߇޽ࠅ‫↪᦭ࠅࠃޔ‬ᕈߩ㜞޿⮎೷ߩഃ಴߇ᦼᓙߐࠇߡ߈ߚ‫ޕ‬
ߎߩࠃ߁ߥ⁁ᴫਅᒰ␠ߢߪᷓ࿷ᕈ⌀⩶∝ࠍ࠲࡯ࠥ࠶࠻ߣߒߡ㉙㉂ᄤὼ‛ߩត⚝ࠍⴕߥ޿‫ޔ‬ᣂⷙߢ࡙
࠾࡯ࠢߥ᭴ㅧࠍ᦭ߔࠆᢙ⒳ߩᄤὼ‛ࠍ⷗಴ߒߚ‫ߜ߁ߩߎޕ‬ᚒ‫ ߪޘ‬FR109615‫ޔ‬FR901469 ߅ࠃ߮
FR901379 ࠍ࡝࡯࠼ൻว‛(ਅ࿑)ߣߒߡㆬᛯߒ‫ޔ‬ᣂⷙߥᷓ࿷ᕈ⌀⩶∝ᴦ≮⮎ߩഃ಴ࠍ⋡ᜰߒߡว
ᚑዷ㐿ࠍ࿑ߞߚ‫ ߦ․ޕ‬FR901469 ߣ FR901379 ߪ⌀⩶ߩ 1,3-E-ࠣ࡞ࠞࡦวᚑ㉂⚛㒖ኂࠍ૞↪ᯏ૞ߣߔ
ࠆ⚦⢩ოวᚑ㒖ኂ‛⾰ߢ޽ࠅ‫⚦ߩ࠻ࡅޔ‬⢩ߦߪ⚦⢩ო߇ሽ࿷ߒߥ޿ߎߣ߆ࠄㆬᛯᲥᕈ߇ᦼᓙߢ߈ߚ‫ޕ‬
FR901379 ⺃ዉ૕ߩ᭴ㅧᵴᕈ⋧㑐⎇ⓥࠍㅢߓߡ‫ޔ‬ᚒ‫㉄ࡦ࠴ࡒ࡞ࡄߪޘ‬஥㎮ߩᄌ឵ߦࠃࠅ᛫⌀⩶ࠬࡍ
ࠢ࠻࡞ߩ᜛ᄢ‫࠳ࠫࡦࠞޔ‬ዻ‫ࠬ࡞ࠡ࡞ࡍࠬࠕޔ‬ዻߦኻߔࠆᵴᕈߩჇᒝ‫ޔ‬૕ౝേᘒߩᡷༀ‫ޔ‬Ქᕈߩシᷫ
ࠍ㆐ᚑߒ‫ޔ‬⢽ṁᕈ஥㎮ㇱಽߦࠗ࠰ࠝࠠࠨ࠱࡯࡞Ⅳࠍ᦭ߔࠆ FK463(ਅ࿑)ࠍ㐿⊒୥⵬ຠߣߒߡㆬᛯߒ
ߚ‫ޕ‬FK463 ߪ⥃ᐥ⹜㛎ߦ߅޿ߡ߽ఝࠇߚ᦭ലᕈߣ቟ోᕈ߇⏕⹺ߐࠇ‫ޔ‬2002 ᐕ 12 ᦬ߦ࿖↥ೋߩ
ࠠࡖࡦ࠺ࠖࡦ♽᛫⌀⩶⮎ߣߒߡ৻⥸ฬ Micafungin‫ޔ‬໡ຠฬ ࡈࠔࡦࠟ࡯࠼ߢ਄Ꮢߐࠇࠆߦ⥋ߞߚ‫ޕ‬
ᧄ⻠Ṷߢߪ਄⸥᛫⌀⩶ᕈᄤὼ‛ߩᦨㆡൻ⎇ⓥߣ Micafungin(FK463)ߩഃ಴⚻✲ߦ㑐ߔࠆ⹦⚦ࠍ⚫
੺ߔࠆ‫ޕ‬
HO
OH
OH
1R
COOH
2S
O
O
H 2N
NH2
N
O H
NH
HCl
O
H
N
O
FR109615
N
O H
N
O H
O
H
N
O
H
N
O
N
HO
OH
OH
H 2N
N
O H
N
O
O
HN
O
OH
NH
OH
O
FR901469
OH
O
N
H2 N
O
O
HO
NH
O
HO
OH
N
H
HN
O
NH N
OH O
HO
OH
OH
H
N
OSO3Na
OO
OH
O
N
H 2N
O
O
HO
OH
N
H
NH
O
HO
O
NH
OH O
OH
HO
N O
OH
H
N
HN
O
O
OH
N
OH
OSO3Na
Micafungin(FK463)
FR901379
O