1、Chemistry in Biomedicine,and Drug Discovery,Professor Ari KoskinenHelsinki University of Technology,11.03.2005,Ari Koskinen Laboratory of Organic Chemistry,Numberapprovedby,FDA,0,24,0,21,7,18,6,16,2,15,5,13,7,12,5,11,8,9,4,8,2,7,6,6,5,5,8,4,$/No.,New Chemical Entities vs. R&D Expedinture$ billions,6
2、0,0,70,50403020100,86 87 88 89 90 91 92 93 94 95 96 97 98 99,0,600,500,400,300,200,100,00,R&D Spending $ billionsNew molecular entities approved by FDA Ratio: $ / No.,Note: Ethical pharmaceuticals only. Expenditures worldwide by U.S.-owned research-based pharmaceutical companies,C&EN January 17, 200
3、0, Food & Drug Administration, Pharmaceutical Research & Manufacturers of America: PhRMA Annual Survey 2000.Ari KoskinenLaboratory of Organic Chemistry,New Drug Development,Ari Koskinen Laboratory of Organic Chemistry,R 2001,Africa,Americas Europe,Asia-Pacific Australia,Middle East Others,Ari Koskin
4、en Laboratory of Organic Chemistry,a,b,$ 1.7 bn (2003) per product is spent on,R&D StageSynthesis/extractionBiological screening/ pharmacological testingToxicology/safetyDosage formulationClinical evaluationProcess development for manufacturing/ quality controlRegulatoryOther,% of spendinga11.016.06
5、.09.634.59.63.89.4,% of employeesb12.918.37.811.624.310.34.810.0,Company financed R&D in US based on 1995 figures totalling $ 11.8 bnUS scientific and professional personnel totaling 34, 784 employeesSource: Pharmaceutical Research & Manufacturers of America, Industry Profile 19972003 data: C&EN 200
6、3, 81 (50), 8.Ari KoskinenLaboratory of Organic Chemistry,Market Exclusivity Times Decrease,Ari Koskinen Laboratory of Organic Chemistry,Development pipeline,Ari Koskinen Laboratory of Organic Chemistry,Top 10 Therapies,December 6, 2004 Volume 82, Number 49,pp. 18-29,Ari Koskinen Laboratory of Organ
7、ic Chemistry,Top 10 Products,December 6, 2004 Volume 82, Number 49,pp. 18-29,Ari Koskinen Laboratory of Organic Chemistry,Mergers,December 6, 2004 Volume 82, Number 49,pp. 18-29,Ari Koskinen Laboratory of Organic Chemistry,Off Patent,December 6, 2004 Volume 82, Number 49,pp. 18-29,Ari Koskinen Labor
8、atory of Organic Chemistry,Patents expiring,December 6, 2004 Volume 82, Number 49,pp. 18-29,Ari Koskinen Laboratory of Organic Chemistry,Promising New Drugs,December 6, 2004 Volume 82, Number 49,pp. 18-29,Ari Koskinen Laboratory of Organic Chemistry,Diversity of Drug Structures,B,O,D,F,E,H,O,O G,Nat
9、ural Products as Drug LeadsO,Me MeO,O,NH,ClHO,OMeO MeA1Me O ClO A,O,MeOHO NO2 Me,O O CO,MeMeOOO MeOH,Me OMeOOO OH OH,OH OGO OMe,O OH O O,O,O OHO,MeA2,OH,MeMeMeO,H,OO,O HOH O O,Me,Me,OMe,Everninomicin 13,384-1,MeCallipeltoside A,Cl,inhibits proliferation of KB and P388 cellsprotects cells infected wi
10、th HIV,O,16,OH,Me,Br,46,OMe43,OH,OMe33 OOH,N 29 O,O,24O,O1,N,O9 O5,HO,O,H,A OOMe,B O H MeC DH OH,EO OH H,HN I Me H H O MeO HFMe,Phorboxazole A,Azaspiracid causative agent for 1995 human poisonings by contaminated Irish musselsMytilus edulisAri KoskinenLaboratory of Organic Chemistry,H,H,O,N,O,S,O O,
11、N,N H O,N,N,H,O,H Me N,H,RCO N NMe S N CN NHH,O,O,N,O,O,Chemical Strategies in Drug DevelopmentIsolationStructure based synthesis,HO,N Rational Drug Design,O,OMe,HO O O,H Design based on Chemical DiversityMeCO2H,Cl,NN N,O,NOH,Morphine-Lactams(antibiotics)MeOOMe NMe,StrychnineBr,splitTagamet Progeste
12、rone (anti-ulcer)MeOMeO OO OMeH,QuinineValium Br(tranquilizer),Ari Koskinen Laboratory of Organic Chemistry,High Throughput Screening,Plants (500 000) Marine natural products (106),Invertebrate natural products (109),Compound libraries Structure based design,Recombinant methods,Peptide libraries Pep
13、tidomimetic libraries,Ari Koskinen Laboratory of Organic Chemistry,Drug Development ParadigmsTraditional ApproachClinical/preclinicalObservations,Disease model,in vivo,LEAD,in vivoStudies onpathophysiologyRational Approachin vitro,Disease gene,or in vivo,Validated target,in vitro,LEAD,design,Transge
14、nic animalsAri KoskinenLaboratory of Organic Chemistry,Drug Development ParadigmsTARGET IDENTIFICATIONGeneral,combinatorial libraries,LEAD GENERATION,Biased combinatorial libraries,LEAD OPTIMIZATION,Structural chemistry,DRUG CANDIDATEAri KoskinenLaboratory of Organic Chemistry,Chemical Diversity,Bas
15、is set of 20,Units203,Library Entities8 000,(e.g. natural amino acids),204,160 000,205Units,3 200 000Library Entities,The number of different chemical entities,N = bx, where x = the number of steps, and b = number of different building blocks.,Basis set of 100 (e.g. carbohydrates),100310041005Units1
16、0003,1 Million100 Million10 BillionLibrary Entities1 Billion,The problem of combinatorial synthesis is not that of making compounds, but that of finding ways to select and identify the compounds:One must be able to extract the information made available by library screening.,Basis set of 1000,(e.g.
17、synthetic building blocks),1000410005,1 Trillion1 Quadrillion,Ari Koskinen Laboratory of Organic Chemistry,Combinatorial Chemistry,solid-phase organic chemistry (SPOC)combinatorial synthesis,structure elucidation based on deconvolution and taggingstructure-diversityautomation,Reviews:Special Issue:
18、Acc. Chem. Res. 1996, 29, # 3 (March). Hermkens, P.H.H.; Ottenheijm, H.C.J.; Rees, D. Tetrahedron 1996, 52, 4527-4554.,Frchtel, 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. Chem
19、tracts: 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.,Ari Koskinen Laboratory of Organic Chemistry,1987,1989,1991,1993,1995,1997,
20、1985,Combinatorial Chemistry PublicationsCombinatorial Chemistry140012001000,#,800 600 400 200,PatentsPublications,0YearAri KoskinenLaboratory of Organic Chemistry,Solid Phase Organic SynthesisPh,Ph,OPhO O,O,O,O,O,1. MeMgI 2. H2O 3. KOH 4. H+,Ph,MeOH,CO2H,Atrolactic acidKawana, M.; Emoto, S. Tetrahe
21、dron Lett. 1972, 4855-4858.,O,O,Scrambled product must arise through intraresin reactions.Intraresin reactions occur even at resin loadings of 0.5 % (0.05,CH2OC (CH2)5 C O CEt3*,mmol/g resin!),O,O,O,O,O,*,*,Et3C,O,*,Resin bound ester,Autocleaved ester,Crowley, J.I.; Rapoport, H. Accts. Chem. Res. 19
22、76, 9, 135-144.Ari KoskinenLaboratory of Organic Chemistry,Combinatorial Library: Split Synthesis Method,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, 82-8
23、4.Divide, Couple and RecombineHoughten, R.A. et al Nature 1991, 354, 84-86.Ari KoskinenLaboratory of Organic Chemistry,a,A,b,B,c,A,B,Construction of an Encoded Synthetic Library,Tags a, b, and c are attached to the same,beads as the growing oligomer chain. The overall structure of the hit oligomer c
24、an 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.,C Tags should have high information content, beamenble to high sensitivity detection anddecoding, and must be chemically orthogonal tothe oligomer protocol.C Single-stranded o
25、ligonucleotides, coupled withPCR amplification: 8.2 x 105 synthetic peptides.,a,b,c,also: Lerner, R.; et al PCT Appl. WO 93/20242.,Nielsen, J. et al. JACS 1993, 115, 9812-9813.POOL,a,A,b,B,c,C,AA,AB,AC,BA,BB,BC,CA,CB,CC,a,a,a,b,a,c,b,a,b,b,b,c,c,a,c,b,c,c,Ari Koskinen Laboratory of Organic Chemistry
26、,Spatially Addressable Parallel Synthesis,h,Mask 1,X,X,X,X,X,X,X,X,A,A,X,X,NH,NH,NH,NH,Deprotect,NH2,NH2,NH,NH,X-A,NH,NH,NH,NH,CouplehMask 2,X,X,E,E,F,F,A,A,X,X,X,X,X,X,C,C,D,D,NH,NH,NH,NH,X-B,A,A,B,B,Repeat,A,A,B,B,CoupleFodor, S.P.A.; Read, J.L.; Pirrung, M.C.; Stryer, L.; Yu, A.T.; Solas, D. Scie
27、nce 1991, 251, 767.Jacobs, J.W.; Fodor, S.P.A. Trends Biotechnol. 1994, 12, 19-26.Ari KoskinenLaboratory of Organic Chemistry,Spatially Addressable Chemical Libraries,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
28、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.,Ari Koskinen Laboratory of Organic Chemi
29、stry,Hydroxylamine ResinOHO N,Ph,O,Ph,O,Ph,Cl,NEt3/DMF,Ph,O N,Omax 1792 and 1743 cm-1,N2H4/THF,PhO NH2PhTetrahedron Lett. 1997, 38, 7233-7236Ari KoskinenLaboratory of Organic Chemistry,Succinyl Amide LibraryOO,PhPh,O NH2,O THF,PhPh,O NH,O,O,OH,RNH2, DCC/HOBtDMF, rt,HO NH,O,O,NHR,HCO2H/THF,PhPh,O NH,
30、O,O,NHR,Ph,Ph,O,OMe,O,OMe,Tetrahedron Lett. 1997, 38, 7233-7236Ari KoskinenLaboratory of Organic Chemistry,Peptidic and Peptidomimetic Libraries,O,R1,PhPh,O NH2,OO 10a, b, c,HO NH,O,R1,O,H N,R2,+,HO NH,O,R1,O,H N,R2,4,11,Compound 10, 11, 12,12,entryR1 =,aMe Ph,bPh,cBn,d,Ph,R2 =,O,OMe,O,OMe,Ph,Ph,Rea
31、gents and conditions: a) 60 C, 6 h, THF; b) (S)-phenylethylamine or amino acid eater hydrochloride/triethylamine, HOBt, DCC (5-fold excess), DMF, 6 h; c) HCO2H/THF (1:3), 1 hScheme 3Tetrahedron Lett. 1997, 38, 7233-7236Ari KoskinenLaboratory of Organic Chemistry,Crude NMR80,70,HO,N H,O,O,H N,O,OMe,6
32、05040O 30N OHO 20100,10,9,8,7,6,5,4,3,2,1,(ppm)Tetrahedron Lett. 1997, 38, 7233-7236Ari KoskinenLaboratory of Organic Chemistry,Analysis,Monitor conversion on bead (e.g. Kaiser test for free primary amines),Analysis of reaction products on bead,Analysis of combinatorial mixtures of products,Ari Kosk
33、inen Laboratory of Organic Chemistry,IR on Bead,1971: 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 pmo
34、les of material,Ari Koskinen Laboratory of Organic Chemistry,IR on BeadFT-IR can monitor progress of reactions:,O,O,O,OH,O,COCl 4,O,4,N,Diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS): fast, no sample preparation (Chan, T.Y. Tetrahedron Lett. 1997, 38, 2821-2824).Ari KoskinenLab
35、oratory of Organic Chemistry,13C:,NMR,low abundance, usually large sample,quantities, long pulsing19F, 31P used also,MAS: nanoprobes allow for 10 mg resin (Sarkar, S.K. J. Am. Chem. Soc. 1996, 118, 2305-2306.),Ari Koskinen Laboratory of Organic Chemistry,Mass spectrometry,MALDI-TOF MS: femtomole sam
36、ples (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),Ari Koskinen Laboratory of Organic Chemistry,Is it feasible to make all possible interestingmolecules combinatorially?Only C,H,N,OAvg mol wt of permeable
37、drugmolecule ca 500; max 750Avogadros number 6.1023Only one molecule each 10200moleculestotal mass: 10173 tonnesweight of Earth: 6.1021 tonnes!,Weight of the Universe: ca 1084,500,Mr,tonnes!Ari KoskinenLaboratory of Organic Chemistry,Challenges in Combinatorial Chemistry,Development of diversity as
38、a conceptDevelopment of solid phase synthesis,Development of fast, chemoselective, high yieldsolution synthesis methods,Development of high speed analysis,Development of efficient screening strategies forminute amounts of compounds in mixtures,Ari Koskinen Laboratory of Organic Chemistry,Ari Koskine
39、n Laboratory of Organic Chemistry,Ari Koskinen Laboratory of Organic Chemistry,More 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.
40、 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:/ Koskinen Laboratory of Organic Chemistry,Target Oriented, Medicinal & Combinatorial and Diversity Oriented Synthes
41、is,Schreiber S.L.; Burke, M.D. Angew.Chem.Int.Ed. 2004 ,43 ,46 58,Ari Koskinen Laboratory of Organic Chemistry,Generating Skeletal Diversity,Schreiber S.L.; Burke, M.D. Angew.Chem.Int.Ed. 2004 ,43 ,46 58,Ari Koskinen Laboratory of Organic Chemistry,Small Molecule Discovery,Schreiber S.L.; Burke, M.D
42、. Angew.Chem.Int.Ed. 2004 ,43 ,46 58,Ari Koskinen Laboratory of Organic Chemistry,Ari Koskinen Laboratory of Organic Chemistry,Complexity of Synthetic Targets, This is where it started!,O,Erythromycin is.,HOHO,O,OH O,NMe2 OH,O,O,so hopelessly difficult that its conquest cannot be conceived within th
43、e foreseeable future (Woodward, 1956),O O OMeOAcErythromycin AAri Koskinen Laboratory of Organic Chemistry,Trends in Synthetic Methodology,PERIOD,TREND,OBJECTIVE/OUTPUT,1950-1960,Classical synthesis Target conquest,Hardware,of natural products Mechanisms, Spectroscopy,1970-1980 R.B. Woodward Nobel 1
44、965 for his outstanding achievements in the art of organic synthesis,Multistep, strategy and transformation based synthesis,Stereo/enantiocontrol Software Synthetic methods,1990-,Designed molecules Selectivity, RecognitionFunction, Intelligence ContentE.J. Corey Nobel 1990for his development of the
45、theoryand methodology of organic synthesisAri KoskinenLaboratory of Organic Chemistry,Ari Koskinen,Binding model,J. Biol. Chem. 1997, 272, 23312-23316Laboratory of Organic Chemistry,Overlay of model & X-ray,Ari Koskinen Laboratory of Organic Chemistry,Calyculin analysis,Koskinen, A.M.P.; Chen. J. Te
46、trahedron Lett. 1991, 32, 6977-6980.Pihko, P.M.; Koskinen, A.M.P.Synlett 1999, 1966-1968.,Pihko, P.M.; Koskinen, A.M.P. J. Org. Chem. 1998, 63, 92-98.,Spiroketal Model Studies,Spiroketal Model Studies,Rauhala, V.; Nevalainen, M.; Koskinen, A.M.P. Tetrahedron 2004, 60, 9199.,Me3Al, THF/CH2Cl,Spiroket
47、al Model Studies,O95 %,O,ONBni) Et3N, Bu2BOTfii) 3-Benzyloxy-propionaldehyde,TBSO,OBn,+,ON OMe,OTBS,i) HNMe(OMe).HCl,1) BuLi, alkyne2) Weinreb amide 297% TBSO OBn O79 %ii) TBSOTf,ImH, CH2Cl2,O,ONOBnBn,OH,O,OBnOTBS,OBn,68%,OBn,OBn,1) CSA, MeOH 2) PhH, p-TsOH3) TEA,BnO,O,O,BnO,O,O,O,O,90 % (1:1)Aiguad
48、e, J.; Hao, J.; Forsyth, C. J. Org. Lett. 2001, 3, 979-982Rauhala, V.; Nevalainen, M.; Koskinen, A.M.P. Tetrahedron 2004, 60, 9199.,C9-C19 Fragment,Karisalmi, K.; Koskinen, A.M.P. Synthesis 2004, 1331-1341.,C9-C19 Fragment,Karisalmi, K.; Koskinen, A.M.P. Synthesis 2004, 1331-1341.,Boron aldol TSs,Be
49、rnardi, A., Gennari, C., Goodman, J. M. and Paterson I. Tetrahedron:Asymmetry 1995, 6, 2613.,C9-C19 FragmentC41O31C4,C3,C2,C1,O10,C5,O6,C11,C16,C8,C9,C7,C21,C12,C13,C14,C15,C9-C19 Fragment,crotylsilylation: Chemler, S. R.; Roush, W. R. J. Org. Chem. 2003, 68, 1319.,Karisalmi, K.; Koskinen, A.M.P. Tetrahedron Lett. 2004, 45, 8245.,Conclusions on I.A.I.,
