Rational Drug Design

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?????????????

• ????????????
• ??????????
• Rational Drug Design
• ?????????

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1. ????????????
???????????/??????? ??????????????
2. ?????????? ADME
i. ?????????,??????,????
RH Flufenazine ????,??????,????1? RCO(CH2)5/8CH3
???/???,????24?
ii. ?????????(???????????)
????(??????,??????)
??????? PC?????????,????????,?????
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iii. ????????? ????????????
Ampicillin,???????,F2030
Pivampicillin
lenampicillin
F95, ??????24X,?????,t1/2?
iv. ???????
Prostaglandin E2 ????E2
?????,?????,???,??????
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3. ??????(Rational Drug design, Lead Optimization)
Lead????,???????,??????? ??????,????????? ????????
???????? ?????,????????????????????????????? ??
???,???????????(??,?????)
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??prodrug

• Albert, A. (1958) ??????,???????????????????????
• Harper 1959??????????,??????????????????????,?????
  ???????????????????
• ??(prodrug)??????????????,??????????,?????????????
  ?????
• ??????(carrier-linked prodrug)
• ????(bioprecursor)
• ?????????(??)?????????????(????????)??????,???????
  ??

??????prodrug(???????)??????(??????????) ????(
????)???(????)
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?????

• ?????????????
• ????????????,????????????
• ?????????????
• ???????????
• ?????????????????????,??????????????,????????,????
  ??????????

?????? ????????? ??????????? ??????????
??????? ?????????????????????
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??1. ????????????

• ???????????40,???????????(98-99)
• ????????????????(? ??15 min)
• ??????????????????,?????????????????
• ????????????????????????
• ????(0.8-1.0g/d)???????(2.0g/d)???
• ?????????????????,???????????????????

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?????????????
?????
?????
??????, ???????
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?????
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??2. ??????
?????
Pamoic acid????
bezathine
????
procaine
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????????????
??24?
Flufenazine(????1?)
?????????-?????N-(2-???)?????????(???)????(???
?)polyK(????)?11-27
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??3. ??????????
(???)
(????????????)
(???)
(????????,??????,????)
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??4. ???????
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??5. ??????
?????????????,??????????
???
Helenalin
Indomethacin????,???? ???(?????????????)
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??6?????????
?????????Site-directed drug delivery
??????????????????? ?????????Site-specific drug
release ??????,??????????????
????
??
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• ????????????????

???? ??????() ?? ?? ??
??? 100 100 1.0
L-?????? 75 250 3.3
?????? 145 60 0.4

• ????-???????????????,???????????????

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Site-specific drug release
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???? Tripartate prodrug
Carrier
Linker
Drug
enzyme
Carrier
Linker
Drug

spontaneously
Linker
Drug

Eg. ???(PTX)-????(PEG)-???(bombesin)
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?????????Antibody-Directed Enzyme Prodrug
Therapy, ADEPT
?????????????? ??,?????????????.????????
????????????????.??????,? ????,????????????????.
Target ????
????? ?
??
??

• ???G2(CPG2)
• ???A
• ?????
• ???
• ??????
• ?-????

MMCI??W14F(ab)2-CPG2(phase I in 2006)

• MMCI??CPG2??????????????????????????????,????????
  ????100???????????????????

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ADEPT-?-Lactamase
?-????
???
??
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????(bioprecursor)
??????,??????????????????????????,????I???????????
???????-???????????
??
Acyclovir F 20
6-deoxyacyclovir F 100 Sw 600X
??
????????? ??????????????????? ?????????
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??????
Go through Table 11-28 for more examples
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?? Soft drug

• ??????????????????,??????,??????
• ???????????????????????,????????,?????????????????
  ????,???????????????(??????????????)
• ????????(?????????)
• ??????????????

• ???????????
• ?????????????
• ???????????????
• ??????????????
• ????????????
• ?????????,??P450???????

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??????????????
????????? ???? LD50 103 mg/kg
Soft analog LD50 4110 mg/kg (Lethal Dose, 50)
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???????????(?????,???,???,g-?????) ???????????????
?,?????????????
cortisone
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??????????????
?????? Remifentanil
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??

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