Applications of combinatorial chemistry to drug design and development

Current Opinion in Drug Discovery and Development

Volumn 2, Issue 4, 1999, Pages 321-331

  Edwards, Paul J ^a  

^a PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United Kingdom)

Author keywords

Combinatorial chemistry; Multi component reactions; Multi target libraries; Polymer assisted solution phase

Indexed keywords

ASPARTIC PROTEINASE; BLOOD CLOTTING FACTOR 10A; CATHEPSIN D; MATRIX METALLOPROTEINASE INHIBITOR; N (9 HYDROXY 9 FLUORENECARBOXY)PROLINE (4 AMINOCYCLOHEXYLMETHYL)AMIDE; PIPERAZINEDIONE; THROMBIN; UNCLASSIFIED DRUG;

ARTICLE; BIOAVAILABILITY; DRUG CONFORMATION; DRUG DESIGN; DRUG EFFICACY; DRUG SYNTHESIS; SOLID PHASE EXTRACTION; THROMBOSIS; X RAY CRYSTALLOGRAPHY;

EID: 0032780036     PISSN: 13676733     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (49)

1. Terrett NK, Gardner M, Gordon DW. Kobylecki RJ, Steele J.Combinatorial synthesis - the design of compound libraries and their application to drug discovery. Tetrahedron (1995) 51(30):8135-8173.
2. Brady SF, Stauffer KJ, Lumma WC, Smith GM, Ramjit HG, Lewis. SD, Lucas BJ, Gardell SJ. Lyle EA, Appleby SD, Cook JJ, Holahan MA, Stranieri MT, Lynch Jr JJ, Un JH, Chen I-W, Vastag K, Naylor-Olsen AM, Vacca JP.Discovery and development of the novel potent orally active thrombin inhibitor W-(9-hydroxy-9-fluorenecarboxy)prolyl trans-4aminocyclohexylmethyl amide (L-372,460).coapplication of structure-based design and rapid multiple analogue synthesis on solid support. J Med Chem (1998) 41:401 -406.
3. • Library synthesis of thrombin inhibitors with the successful outcome of producing compounds with oral bioavailability.
4. Lumma Jr WC, Witherup KM, Tucker TJ, Brady SF, Sisko JT, Naylor-Olsen AM, Lewis SD, Lucas BJ, Vacca JP.Design of novel, potent, noncovalent inhibitors of thrpmbin with nonbasic P-1 substructures.rapid structure-activity studies by solid-phase synthesis. J Med Chem (1998) 41:1011-1013.
5. Mohan R, Yun W, Buckman BO, LJang A, Trinh L, Morrissey MM.Solid-phase synthesis of W-substituted aminophenoxy pyridines as factor Xa inhibitors. Bioorg Med Chem Lett (1998) 8:1877-1882.
6. Stürzebecher J, Stürzebecher U, Vieweg H, Wagner G, Hauptmann J, Markwardt P.Synthetic Inhibitors of bovine factor Xa and thrombin. Comparison of their anticoagulant efficiency. Thromb Res (1989) 54:245-252.
7. Ogbu CO, Qabar MN, Boatman PD, Urban J, Meara JP, Ferguson MD, Tulinsky J, Lum C, Babu S, Blaskovich MA, Nakanishi H, Ruan F, Cao B, Minarik R, Little T, Nelson S, Nguyen M, Gall A, Kahn M.Highly efficient and versatile synthesis of libraries of constrained -strand mimetics. Bioorg Med Chem Lett (1998) 8:2321 -2326.
8. Carroll CD, Patel H, Johnson TO, Quo T, Ortowski M, He Z-M, Cavallaro CL, Quo J, Oksman A, Gluzman IY, Connelly J, Chelsky D, Goldberg DE, Dolle RE.Identification of potent Inhibitors of plasmodium falciparum plasmepsin II from an encoded statine combinatorial library. Bioorg Med Chem Lett (1998) 8:2315-2320.
9. Carroll CD, Johnson TO, Tao S, Lauri G, Oriowski M, Gluzman IY, Goldberg DE, Dolle RE.Evaluation of a structure-based statine cyclic diamino amide encoded combinatorial library against plasmepsin II and cathepsin D. Bioorg Med Chem Lett (1998) 8:3203-3206.
10. • Emphasis placed on the design of a large synthesized combinatorial library aimed at eliciting SAR data for plasmepsins I and II.
11. Lee CE, Kick EK, Ellman JA.General solid-phase synthesis approach to prepare mechanism-based aspartyl protease inhibitor libraries. Identification of potent cathepsin D inhibitors. J Am Chem Soc (1998) 120:9735-9747.
12. •• Preparation of a library of statine based inhibitors of cathepsin D from complex solid-phase chemistry based upon mechanistic design principals.
13. Szardenings AK, Harris D, Lam S, Shi L, Tien D, Wang Y, Patel DV, Navre M, Campbell DA.Rational design and combinatorial evaluation of enzyme inhibitor scaffolds.identification of novel inhibitors of matrix metal loproteinases. JMed Chem (1998) 41:2194-2200.
14. Bums, CJ, Groneberg RD, Salvino JM, McGeehan G, Condon SM, Morris R, Morrissette M, Mathew R, Dambrough S, Neuenschwander K, Scotese A, Djuric SW, Ullrich J, Labaudiniere R.Nanomolar inhibitors for two distinct biological target families from a single synthetic sequence.A next step In combinatorial library design? Angew Chem Int Ed Engl (1998) 37:2848-2850.
15. •• This paper presents the interesting concept of compounds originating from single library chemistry, which are targeted at multiple biological targets by careful design of compounds to be synthesized.
16. Vesely J, Havlicek L, Stmad M, Blow JJ, Donella-Deana A, Pinna L, Letham DS, Kato J-Y, Delivaud L, LeClerc S.Inhibition of cyclin-dependent kinases by purine analogues. EurJBiochem (1994) 224(2):771-786.
17. Gray NS, Wodicka L, Thunnissen AM, Norman TC, Kwon S, Espinoza FH, Morgan DO, Bames G, LeClerc S, Meijer L, Kim S-H, Lockhart DJ, Schulte PG.Exploiting chemical libraries, structure, and genomics In the search for kinase Inhibitors. Science (1998) 281(5376):533-538.
18. •• This publication describes the current state of art in the design of a targeted library based on a pharmacophore model. The chemical procedures can be found in the pertinent references. It also highlights the current state of art in lead discovery using combinatorial libraries.
19. Augeri DJ, O'Connor SJ, Janowick D, Szczepankiewicz B, Sullivan G, Larsen J, Kalvin D, Cohen J, Devine E, Zhang H, Cherian S, Saeed B, Ng S-C, Rosenberg S.Potent and selective non-cysteine-containing inhibitors of protein farnesyltransf erase. JMed Chem (1998) 41(22):4288-4300.
20. • The structure of the newly discovered lead compound was further modified as part of a medicinal chemistry program. The biological activity was improved up to an /CA of 0.4 nM.
21. Sun J, Qian Y, Hamilton AD, Sebti SM.Ras CAAX peptidomimetic FTI276 selectively blocks tumor growth in nude mice of a human lung carcinoma with K-Ras mutation and p53 deletion. Cancer Res (1995) 55(19):42434247.
22. Révész L, Bonne F, Manning U, Zuber J-F.Solid phase synthesis of a biased mini tetrapeptoid-library. for the discovery of monodentate ITAM mimics as ZAP-70 inhibitors. Bioorg Med Chem Lett (1998) 8(5):405-408.
23. Simon RJ, Kania RS, Zuckenmann RN, Huebner VD, Jewel! DA, Banville S, Ng S, Wang L, Rosenberg S, Martowe CK, Spellmeyer D, Tan R, Frankel AD, Santi DV, Cohen FE, Bartlett PA.Peptoids.a modular approach to drug discovery. Proc Natl Acad Sei USA (1992) 89(20):9367-9371.
24. Nicolaou KG, Winssinger N, Vourtoumis D, Ohshima T, Kim S, Pfefferkorn J, Xu J-Y, Li T.Solid and solution phase synthesis and biological evaluation of combinatorial sarcodictyin libraries. J Am Chem Soc (1998) 120:1081410826.
25. •• To date, only a few publications have been concerned with the construction of libraries of large molecules. This paper represents one of the first examples of a solid-phase protocol used for introducing diverse side chains to a scaffold based on a natural product.
26. Wong C-H, Ye X-S, Zhang Z.Assembly of oligosaccharide libraries with a designed building block and an efficient orthogonal protection-deprotection strategy. J Am Chem Soc (1998) 120(28):7137-7138.
27. Nicolaou KG, Watanabe N, Li J, Pastor J, Winssinger N.Solid phase synthesis of oligosaccharides.construction of a dodecasaccharide. Angew Chem Int Ed Engl (1998) 37(11):1559-1561.
28. • This paper reports a few examples of successfully synthesized oligosaccharides. The authors are still to prove their concept during the preparation of a large library of oligosaccharides.
29. Hulme C, Morrissette MM, Volz FA, Bums C.The solution phase synthesis of diketppiperazine libraries via the Ugi reaction.Novel application of Armstrong's convertible Isonitrile. Tetrahedron Lett (1998) 39(10):1113-1116.
30. • The authors also successfully applied this Ugi/de-Boc/cyclization strategy to the synthesis of ketopiperazines and benzodiazepines.
31. Keating TA, Armstrong RW.Postcondensation modifications of Ugi four-component condensation products.1-lsocyanocyclohexene as a convertible isocyanide. Mechanism of conversion, synthesis of diverse structures, and demonstration of resin capture. J Am Chem Soc (1996) 118(11 ):2574-2583.
32. Fokas D, Ryan WJ, Casebier DS, Coffen DL.Solution phase synthesis of a splro[pyrrolidine-2,3'-oxindole] library via a three component 1,3-dipolar cycloaddition reaction. Tetrahedron Lett (1998) 39(16):2235-2238.
33. • One of the first examples of the use of cycloadditions for the construction of a large library.
34. Powers DG. Casebier DS, Fokas D, Ryan WJ, Troth JR, Coffen DL.Automated parallel synthesis of chalcone-based screening libraries. Tetrahedron (1998) 54(16):4085~4096.
35. Zeng L, Wang X, Wang T, Kassel DB.New developments in automated Prep LCMS extends the robustness and utility of the method for compound library analysis and purification. Comb Chem High Throughput Screening (1998) 1(2):101-111.
36. •• This paper reviews the latest LC-MS developments at CombiChem Inc. The strategy involves fraction collection using mass-triggering which minimizes the number of selected fractions and associated data tracking.
37. Schultz L, Garr CD, Cameron LM, Bukowski J.High throughput purification of combinatorial libraries. Bioorg MedChem J.eff (1998) 8(17):2409-2414.
38. •• This paper outlines the library purification strategy used at MDS Panlabs. In comparison with [25], the authors prefer fraction collection using UV detection and subsequent post analysis using MS. This allows for re-analysis of fractions and the fortuitous registration of explainable by-products.
39. Flynn DL, Devraj RV, Parïow JJ.Recent advances in polymer-assisted solution-phase chemical library synthesis and purification. Curr Opin Drug Discov Dev (1998)1(1):41-50.
40. •• This paper is a comprehensive review of recent developments in polymer assisted solution-phase (PASP) synthesis, complete with tables of applications and leading references.
41. Ferritto R, Seneci P.High throughput purification methods in combinatorial solution phase synthesis. Drugs Future (1998)23(6):643-654.
42. • This review compares the key purification techniques available to the combinatorial chemist to date. Key examples for each method are illustrated.
43. Craston D, Cowen S.The laboratory on a chip.a new approach to chemical analysis and beyond. Sei Prog (1998) 81(3):225-244.
44. •• A review of recent advances in micro engineering with leading references. The authors explain and discuss each technology with regard to its potential applications.
45. Bernard D, Robins I.Microfluidics chemical reactions on a chip. Spec Chem (1998) 18(4):174-177.
46. • This paper outlines the applications of microfluidics to chemical reactions in microreaders and details early successes in its development.
47. For more information on Molecular Simulations Inc products, see http^/www.msi.com/
48. For more information on Oxford Molecular Group, see httptfwww.oxmol.co.uk/
49. For more information on Tripos Inc products and services, see httpMvww. tripos, com/