????:???1,2?7:50am~9:20am

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• ???????1,2?750am920am
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• ??????(?3?) ???,?????
• ???????????,??Thurston, D.E., ?? ???,???????
• ????(?6?)??,???????
• ????(?2?)???,???????
• ?????????,Stephen Neidle, ?????
• ???? 70,??30
• ???? http//bionmr.ustc.edu.cn/courses/

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Agenda

1. ???????? ?????????????????????????????????
2. ???????(?????????????????,???????)
3. ?????PKPD(???????????????????????????)
4. ???????(??????????????????????????)
5. ????(?????DNA?????????????????????)
6. ??????(?????????????????????NO???????????)
7. ??????

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Pharmaceutical Industry
Revenue (2009) 45B Employees 99.8K
Revenue (2009) 62B Employees 115.5K
Revenue (2009) 50B Employees 116.5K
Revenue (2009) 32.8B Employees 63K
Revenue (2009) 45B Employees 99.9K
Revenue (2009) 44B Employees 105K
Revenue (2009) 21.8B Employees 40.4K
Revenue (2009) 30.7B Employees 73K
Revenue (2008) 23.8B Employees 55.2K
Revenue (2009) 18.8B Employees 28K
0.5M / employee
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1.1 ??????
1980??????
????(Research)
????????
Drug Candidate
Lead optimization
????
???????
Hit to Lead
1980
?????
?????
????(Development)
?????? ???????????
Phase III
Phase II
Phase I
??
Preclinical Development
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???????????
?????????????
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1.2 Drug Discovery Process
-




Phase III
Phase II
Phase I
LeadGeneration
Lead Optimisation
Preclinical Development
Target Identification

• High Risk, High investment, High reward
• gt1 billion, 12 years!
• Development is far more expensive than discovery
  dont fail late
• Discovery bottlenecks
• Validated targets
• Quality Hits subsequent Leads
• Optimisation of the Leads
• Only quality compounds should leave Discovery
  (??10????????90???)

Launch
Paul et al, Nature Reviews Drug Discovery, 2010,
9, 203
7
(No Transcript)
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1.2.1 ???????????
?
?
?

???? ????????????????????,??,?????????? ?????????????????,??,?????????? ??????????????????,??,??????????
???? (assay feasibility) ?????????,??????????? ?????????,??????????? ????????????,?????????????????
??? ???????,?????????????? ???????????????? ????????????????,??????????????????????????????????
?? ???????,?????,?????????????????? ???????,??????,?????????????????? ???????????,??????????????????
???? ???????????????? ?????????????,????????(??2.3?),?????????????? ???????-?????????
Frearson et al. Trends in Parasitology 2007
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???????????
Pioneering drug Follow-on drug (me-too / me better)
?? First in class Best in class
?? ?? ??
???? ?? ??
???? ? ??
?? ????,???,??? ????,????,????
??? ?? ??

• ???????
• ????????????
• ????,????
• ??????????
• IP

Sidenafil (Viagra)
Vardenafil
??PDE5 (phosphodiesterase type 5)
Udenafil
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?????

• ??????
• ???????????? (?12-3)
• ?????????GPCR
• ????????Kinase????????
• ?????????????
• ??????????/??????????

Lapatinib (breast cancer)EGFR/HER2 kinase ???
Terbogrel(???)?????A2???????A2??
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????(New Drug Indication)

• ???(Promiscuity)
• Selective Optimization of side activity (SOSA)
• ????????????
• ??????????
• ???
• ?????/?????

5-HT
????????????? ???????5-HT6A?????
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1.2.2 ????
1800s ??????????(??--gt?? ??--gt???) 1960s
???????? 1970s ????,???????? 1980s
?????????(SBDD) 1990s ????,?????(HTS) 2000s
?????????(FBDD)
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Where Do Leads Come From?
Leads
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1.2.3 ??????????? (hit to lead)
?????????????????????????????????????????????????
?????? ??????????????? ????
LE RTln(KD)/HAC LE improves from 0.3 to 0.5
during hits to leads (H2L)
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??????HTS???????
Profile Component Target Claim
Indications What are you treating how
In vitro activity MOA IC50 vs target GI50 Co-dosing?
PKDM Low drugdrug interaction potential (IC50 Cyp450 gt10 mM) hERG IC50 gt30 mM Good metabolic stability in selected species Low to moderate Cl with acceptable t1/2 Formulation
Preclinical Activity Target Modulation Tolerability cf with dose Single or co-dose
Toxicity Acceptable therapeutic window
Dose Regimen Route i.v. or oral? Once-a-day/week dosing interval? Dosed with another compound?
????????p558?12-1
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1.2.4 ???????(LO)

• ???????? ??????????, i.e., homolog/isoform,
  ?????? ????
• ????????????????????
• ?????????????P450,????????CYP????????????????????
  ???????????????
• ???????????????????????????(bioavailability),????
  ??????????(Cmax,Tmax,AUC),??????????
• ????????????????-???,??????????
• ???????????(??)???????????/??,???????????hERG????
  ??????

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Ligand Drug

• A Drug
• Meets (unmet) medical need
• Not adversely toxic for the disease it is
  treating
• Potent in vivo, appropriate duration of action
  low dose
• Selective for the target(s)
• Can be manufactured readily (acceptable cost of
  goods)
• Patentable
• A Ligand (eg inhibitor, lead)
• High affinity for the target in vitro
• Depends on optimal molecular properties (shape,
  electronics) for interaction with the active site
  determined by Structure Activity Relationships
  (SAR)

All depend on the physiochemical properties,
i.e., structure of the compounds
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The Heart of Drug Discovery
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Lead Generation
3 4 years
Lead Generation
Target ID Selection
Candidate Drug
Hit Identification
Lead Identification
Lead Optimisation
HI
LI
LO
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1.2.5 New Drugs

• ??????????????????????,????????????????(??????)
• ????? NCE (new chemical entities)
• ????????????

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• 1???????,??????????,?? ??NCE
• 2??????,?? IND(investigational new drug)
• ?????22?(????,25?)
• ?????19?(????,22?)
• 3?????(?????),?? NDA(new drug approval)
• Phase I 20-30??????
• Phase II ???100?????
• Phase III ???300???
• 4??????,????
• ??????,Phase IV gt2000?

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????
????
??? ??
??
I ?
II ?
III ?
IV ?
???15?
23
(No Transcript)
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(No Transcript)
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Nature Reviews Drug Discovery 12, 569 (2013)
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Atorvastatin
Simvastatin
Lansoprazole
Erythropoietin
Olanzapine
Erythropoietin
Esomeprazole
Sertraline
Celecoxib
Gabapentin
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?? ????(Medicinal Chemistry)???????????????????,?
???????????,??????,?????????,?????????????????????
???? ??????????????? ???? ?????????????????????
????????????? ??????????????,??????????,?????????
??????
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• ????
• ???????(????????????????????????????????????????
  )
• ???????(????????????????????????????????????????
  ???????????????????)
• ???????

???????????,??????

• ??????
• ???
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• ?????

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• ??????
• ???(targets) ??(??),??(receptors), ?(enzymes),
  ??(nucleic acids), ?????????(binding pocket,
  active site) ???????
• ??????
• ????????? (??????????,????--gt?????(New chemical
  entities, NCE)
• ????
• ??????????????????(CNS)????????????

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1.3 ????

1. ????

IUPAC Name
(3R,5R)-7-2-(4-fluorophenyl)-3-phenyl-4-(phenylca
rbamoyl)- 5-(propan-2-yl)- 1H-pyrrol-1-yl-3,5-dih
ydroxyheptanoic acid
SMILES
2. ???????(??????WHO??) International
Nonproprietary Names for Pharmaceutical
Substances, INN) Atovastatin 3. ???????? 4. ???
Lipitor (????140???)