Challenges for Chemistry in Biomedicine and Drug Discovery 2007.pdf$ 1.7 1.7 bbnn (2003)(2003) per...

Challenges for Chemistry in Biomedicine and Drug

Discovery

Challenges for Chemistry in Biomedicine and Drug

Discovery

Professor Ari KoskinenHelsinki University of Technology

20.02.2007

Ari KoskinenLaboratory of Organic Chemistry

FDA Approvals

The R&D Process


New Drug DevelopmentNew Drug DevelopmentNew Drug Development


Investment on R&DInvestment on R&DInvestment on R&D


R&D By Geographic Area; 2004R&D By Geographic Area; 2004R&D By Geographic Area; 2004

AfricaAmericasEuropeAsia-PacificAustraliaMiddle EastOthers


Making Money Out of It?Making Money Out of It?Making Money Out of It?


$ 1.7 bn (2003) per product is spent on$ 1.7 $ 1.7 bnbn (2003) per product is spent (2003) per product is spent onon

R&D Stage % of spendinga % of employeesb

Synthesis/extraction 11.0 12.9

Biological screening/pharmacological testing

16.0 18.3

Toxicology/safety 6.0 7.8

Dosage formulation 9.6 11.6

Clinical evaluation 34.5 24.3

Process development formanufacturing/ qualitycontrol

9.6 10.3

Regulatory 3.8 4.8

Other 9.4 10.0

a Company financed R&D in US based on 1995 figures totalling $ 11.8 bnb US scientific and professional personnel totaling 34, 784 employeesSource: Pharmaceutical Research & Manufacturers of America, Industry Profile 1997

2003 data: C&EN 2003, 81 (50), 8.


Market Exclusivity Times DecreaseMarket Exclusivity Times DecreaseMarket Exclusivity Times Decrease


Development pipelineDevelopment pipelineDevelopment pipeline


Late Stage PipelineLate Stage PipelineLate Stage Pipeline


New Medicines in DevelopmentNew Medicines in DevelopmentNew Medicines in Development


Top 10 TherapiesTop 10 TherapiesTop 10 TherapiesDecember 6, 2005

Volume 83, Number 49

pp. 18-29


Top 10 CompaniesTop 10 CompaniesTop 10 Companies


Top 10 ProductsTop 10 ProductsTop 10 ProductsDecember 6, 2005


pp. 18-29


MergersMergersMergersDecember 6, 2004


pp. 18-29


Off PatentOff PatentOff PatentDecember 6, 2004


pp. 18-29


Patents expiringPatents expiringPatents expiringDecember 6, 2004


pp. 18-29


Promising New DrugsPromising New DrugsPromising New DrugsDecember 6, 2004


pp. 18-29


Generics Share of Rx DrugsGenerics Share of Rx DrugsGenerics Share of Rx Drugs


When to License?When to License?When to License?

Diversity of Drug Diversity of Drug StructuresStructures


Natural Products as Drug LeadsNatural Products as Drug Natural Products as Drug LeadsLeads

Cl

HOCl

OMe

Me

O

OO

O

O

Me OMe

OO

O

O O

O

MeO O

O

O

O

O

O

O

O

OO

O

HO

O Me

OH

Me

MeNO2

HO

Me

MeOH

Me

OH

OMe OH

OMeOH

Me

A1 A2

A

B C D F H

OHO

O OO

O

Me

O

Me

OOO

HN

Me

Me

OH

Me

Me

H

H

H H

OH H

H

H

AB

C DF

H

I

BrOMe

OOH

OMe

N

O

O

O

O

O

N

O

O

OH

OH

O

O

Me

MeO

Me

MeOO

NHO

O

Cl

H OHO

MeO

Me

Me

H

Everninomicin 13,384-1

E G

E G

Azaspiracidcausative agent for 1995 human poisonings by contaminated Irish mussels

Mytilus edulis

1

16

242933

4346

Phorboxazole A

5

9

Callipeltoside Ainhibits proliferation of KB and P388 cells

protects cells infected with HIV


Chemical Strategies in Drug DevelopmentChemical Strategies in Drug Chemical Strategies in Drug DevelopmentDevelopment

IsolationStructure based synthesisRational Drug DesignDesign based on Chemical DiversityO NMe

HO

HO

N

N

O OH

H

H

H O

O

Progesterone

NOH

NOMe

Morphine Strychnine Quinine

N

S

O

HN

CO2H

RCO

NH

N

NH

CN

S N

HN

N

NO

Cl

Tagamet(anti-ulcer)

Valium(tranquilizer)

β-Lactams(antibiotics)

O

NH

O O

Me

Me

O

N

O O

Me

Me Br

Me

O

NH

O O

Me

Me O

OOO

Me

OBr

split


High Throughput ScreeningHigh Throughput ScreeningHigh Throughput Screening

Plants (500 000)Marine natural products (106)Invertebrate natural products (109)Compound librariesStructure based designRecombinant methodsPeptide librariesPeptidomimeticlibraries


Drug Development ParadigmsDrug Development ParadigmsDrug Development Paradigms

in vivo

in vitroor in vivo

designdesignin vitro

in vivo

Studies on pathophysiology

Clinical/preclinical Observations

Disease gene

Transgenic animals

Traditional Approach

Rational Approach

Disease model

Validated target LEAD

LEAD


Drug Development ParadigmsDrug Development ParadigmsDrug Development ParadigmsTARGET IDENTIFICATION

LEAD GENERATION

LEAD OPTIMIZATION

DRUG CANDIDATE

Generalcombinatoriallibraries

Biasedcombinatoriallibraries

Structuralchemistry


Chemical DiversityChemical DiversityChemical DiversityLibrary EntitiesUnits

8 000

160 000

3 200 000

203

204

205

Units Library Entities

1 Million

100 Million

10 Billion1005

1003

1004

Units Library Entities

10003

10004

10005

1 Trillion

1 Billion

1 Quadrillion

Basis set of 20(e.g. natural amino acids)

Basis set of 100(e.g. carbohydrates)

Basis set of 1000(e.g. synthetic building blocks)

The number of different chemical entities,N = bx, where x = the number of steps,

and b = number of different building blocks.

The problem of combinatorial synthesisis not that of making compounds, butthat of finding ways to selectand identify the compounds:

One must be able to extract the informationmade available by library screening.


Combinatorial ChemistryCombinatorial ChemistryCombinatorial Chemistry• solid-phase organic chemistry (SPOC)• combinatorial synthesis• structure elucidation based on deconvolution and tagging• structure-diversity• automation

Reviews:Special Issue: Acc. Chem. Res. 1996, 29, # 3 (March).

Hermkens, P.H.H.; Ottenheijm, H.C.J.; Rees, D. Tetrahedron 1996, 52, 4527-4554.Früchtel, J.S.; Jung, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 17-42.

Lowe, G. Chem. Soc. Rev. 1995, 24, 309.Ellman, J. Chemtracts: Organic Chemistry 1995, 8, 1-4.

Pirrung, M.C. Chemtracts: Organic Chemistry 1995, 8, 5-12.Czarnik, A.W. Chemtracts: Organic Chemistry 1995, 8, 13-18.Mitscher, L.A. Chemtracts: Organic Chemistry 1995, 8, 19-25.

Dolle, R.E.; Nelson, K.H. J. Combinator. Chem. 1999, 1, 235-282.


Combinatorial Chemistry PublicationsCombinatorial Chemistry PublicationsCombinatorial Chemistry Publications

0200400600800

100012001400

#

1985

1987

1989

1991

1993

1995

1997

Year

Combinatorial Chemistry

PatentsPublications


Solid Phase Organic SynthesisSolid Phase Organic SynthesisSolid Phase Organic Synthesis

Kawana, M.; Emoto, S. Tetrahedron Lett. 1972, 4855-4858.

Scrambled product must arise through intraresinreactions.

Intraresin reactions occur even at resin loadings of 0.5 % (0.05 mmol/g resin!)

Crowley, J.I.; Rapoport, H. Accts. Chem. Res. 1976, 9, 135-144.

1. MeMgI2. H2O3. KOH4. H+

Atrolactic acid

O

OO

O

OPh

Ph

PhOO

Ph

OH

CO2H

Me

*

***

Autocleaved esterResin boundester

OO

O

OO

OEt3C

CH2OCO

(CH2)5 CO

O CEt3


Combinatorial Library: Split Synthesis MethodCombinatorial Library: Split Synthesis Combinatorial Library: Split Synthesis MethodMethod

Portioning-mixingFurka, A. et al. Int. J. Pept. Protein Res. 1991, 37, 487-493.Furka, A. et al. Bioorg. Med. Chem. Lett. 1993, 3, 413-418.

Split SynthesisHruby, V.J. et al. Nature, 1991, 354, 82-84.

Divide, Couple and RecombineHoughten, R.A. et al Nature 1991, 354, 84-86.


Construction of an Encoded Synthetic LibraryConstruction of an Encoded Synthetic Construction of an Encoded Synthetic LibraryLibrary

Tags should have high information content, be amenble to high sensitivity detection and decoding, and must be chemically orthogonal to the oligomer protocol.

Single-stranded oligonucleotides, coupled with PCR amplification: 8.2 x 105 synthetic peptides.

also: Lerner, R.; et al PCT Appl. WO 93/20242.

Nielsen, J. et al. JACS 1993, 115, 9812-9813.

Tags a, b, and c are attached to the same beads as the growing oligomer chain. The overall structure of the ‘hit’ oligomer can then be read from the tag information.

Dower, W.J. et al. PCT Appl. WO 93/06121.Needels, M.N. et al. PNAS 1993, 90,

10700.

CBA

POOL

CBA

a b c

a b c

cb aaa a

A

A

A

B

A

C

b c

B CA

a

cbb b ba

B

C

B

B

B

A

ccc b

C

C

C

B

C

A

c a


Spatially Addressable Parallel SynthesisSpatially Addressable Parallel Spatially Addressable Parallel SynthesisSynthesis

Fodor, S.P.A.; Read, J.L.; Pirrung, M.C.; Stryer, L.; Yu, A.T.; Solas, D. Science 1991, 251, 767.Jacobs, J.W.; Fodor, S.P.A. Trends Biotechnol. 1994, 12, 19-26.

hν

NHX

NHXX

NHXNH

hν

NHX

NHAA

NHXNH

X X

BD

ACC

ADB

E E F F

RepeatBX

AXX

AXB

Couple

X-B

Mask 2

Couple

X-ADeprotect NHX

NHAA

NHXNH

X XMask 1

NHX

NH2NH2XNH


Spatially Addressable Chemical LibrariesSpatially Addressable Chemical Spatially Addressable Chemical LibrariesLibraries

Fodor, S.P.A.; Read, J.L.; Pirrung, M.C.; Stryer, L.; Yu, A.T.; Solas, D. Science 1991, 251, 767.Jacobs, J.W.; Fodor, S.P.A. Trends Biotechnol. 1994, 12, 19-26.

Pirrung, M.C.; Read, J.L.; Fodor, S.P.A.; Stryer, L. U.S. Pat 5,143,854, 1992.Holmes, C.P.; Fodor, S.P.A. In Innovation and Perspectives in Solid Phase Synthesis and

Complementary Technologies; Epton, R., Ed., Intercept, UK, 1994.


Hydroxylamine ResinHydroxylamine ResinHydroxylamine Resin

νmax 1792 and 1743 cm-1

Tetrahedron Lett. 1997, 38, 7233-7236

Ph

PhCl

N

O

O

HO

Ph

PhN

O

O

O

Ph

PhNH2O

NEt3/DMF

N2H4/THF


Succinyl Amide LibrarySuccinylSuccinyl Amide LibraryAmide Library


O

O

O Ph

PhNH

O

Ph

PhNH2O

THF

OOH

O

RNH2, DCC/HOBt

DMF, rt

Ph

PhNH

O

ONHR

O

HCO2H/THFNH

HO

ONHR

O

PhOMe

O

OMe

O

Ph


Peptidic and Peptidomimetic LibrariesPeptidic and Peptidomimetic Peptidic and Peptidomimetic LibrariesLibraries

Ph

Ph

O NH2 HO N H

OH N

O

O

O

O

a, b, c

10

4 11

R1

R2 HO N H

OH N

OR2

R1

R1

12

+

OMeOMe

Ph Ph

Ph

OO

Me Ph BnPh

a b c dentry

R1 =

R2 =

Compound 10, 11, 12

a) 60 °C, 6 h, THF; b) (S)-phenylethylamine or amino acid eater hydrochlortriethylamine, HOBt, DCC (5-fold excess), DMF, 6 h; c) HCO2H/THF (1:3), 1 h

Reagents and conditions:

Scheme 3Tetrahedron Lett. 1997, 38, 7233-7236


Crude NMRCrude NMRCrude NMR

(ppm)

1 2 3 4 5 6 7 8 910 0

10

20

30

40

50

60

70

80

NH

OHO

HN

OOMe

O

N

O

O

OH



AnalysisAnalysisAnalysisMonitor conversion on bead (e.g. Kaiser test for free primary amines)Analysis of reaction products on beadAnalysis of combinatorial mixtures of products


IR on BeadIR on BeadIR on Bead1971: resin beads of chloromethyl polystyrene oxidation products in KBr disks (Frechet J.M. J. Am. Chem. Soc. 1971, 93, 492-496.)FT-IR microspectroscopy: single bead from rxn to IR microscopy (Yan, R. J. Org. Chem.1995, 60, 5736-5738.Down to < 100 pmoles of material


IR on BeadIR on BeadIR on BeadFT-IR can monitor progress of reactions:

Diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS): fast, no sample preparation (Chan, T.Y. Tetrahedron Lett. 1997, 38, 2821-2824).

OH O

OCOCl4

O

O

4N

O


NMRNMRNMR13C: low abundance, usually large sample quantities, long pulsing19F, 31P used alsoMAS: nanoprobes allow for 10 mg resin (Sarkar, S.K. J. Am. Chem. Soc. 1996, 118, 2305-2306.)


Mass spectrometryMass spectrometryMass spectrometryMALDI-TOF MS: femtomole samples (Zambias, 1994, TOF-SIMS (Brummel, C.L. Science 1994, 264, 399-402)CE-ESI MS (Dunayevskiy, Y.M. Proc. Natl. Acad. Sci. 1996, 93, 6152-6157)


Is it feasible to make all possible interesting molecules combinatorially?Is it feasible to make all possible Is it feasible to make all possible interesting molecules interesting molecules combinatoriallycombinatorially??

Mr500

•Only C,H,N,O

•Avg mol wt of permeable drug

molecule ca 500; max 750

•Avogadro’s number 6.1023

•Only one molecule each 10200

molecules

•total mass: 10173 tonnes

•weight of Earth: 6.1021 tonnes!

•Weight of the Universe: ca 1084

tonnes!!!


Challenges in Combinatorial ChemistryChallengesChallenges inin Combinatorial ChemistryCombinatorial Chemistry

• Development of diversity as a concept

• Development of solid phase synthesis

• Development of fast, chemoselective, high yield solution synthesis methods

• Development of high speed analysis

Development of efficient screening strategies for minute amounts of compounds in mixtures


More SourcesMore SourcesMore Sources

Reviews:Dolle, R.E.; Kingsley, N.K. J. Combin. Chem. 1999, 1, 235-282.Terrett, N.K. Combinatorial Chemistry OUP 1998, 186 pp.Thompson & Ellman Chem. Rev. 1996, 96, 555-600.Fruchtel & Jung Angew. Chem., Int. Ed. Engl. 1996, 35, 17-42.

Asymmetric Catalysts:Liu & Ellman J. Org. Chem. 1995, 60, 7712-7713.

Web:Tetrahedron Information System

Molecular Diversity: Diversity Lovers’ Forum; http://vesta.pd.com/

http://vesta.pd.com/

Challenges for Chemistry in Biomedicine and Drug DiscoveryFDA ApprovalsThe R&D ProcessNew Drug DevelopmentInvestment on R&DR&D By Geographic Area; 2004Making Money Out of It?$ 1.7 bn (2003) per product is spent onMarket Exclusivity Times DecreaseDevelopment pipelineLate Stage PipelineNew Medicines in DevelopmentTop 10 TherapiesTop 10 CompaniesTop 10 ProductsMergersOff PatentPatents expiringPromising New DrugsGenerics Share of Rx DrugsWhen to License?Natural Products as Drug LeadsChemical Strategies in Drug DevelopmentHigh Throughput ScreeningDrug Development ParadigmsDrug Development ParadigmsChemical DiversityCombinatorial ChemistryCombinatorial Chemistry PublicationsSolid Phase Organic SynthesisCombinatorial Library: Split Synthesis MethodConstruction of an Encoded Synthetic LibrarySpatially Addressable Parallel SynthesisSpatially Addressable Chemical LibrariesHydroxylamine ResinSuccinyl Amide LibraryPeptidic and Peptidomimetic LibrariesCrude NMRAnalysisIR on BeadIR on BeadNMRMass spectrometryIs it feasible to make all possible interesting molecules combinatorially?Challenges in Combinatorial ChemistryMore Sources

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