pharmaceutical industry- drug discovery

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1 ombinatorial hemistry: molecular diversity "Synthesis and pplications of Small Molecule Libraries." Thompson, L..; llman, J.. hem. ev.,, -00. "esign, Synthesis, and valuation of Small-Molecule Libraries. llman, J.. cc. hem. es.,, -. ombinatorial hemistry, icholas K. Terrett, xford University Press, London, pharmaceutical industry- drug discovery Lead mpd optimization (synthesis) rug 0 years $ million $ $ $ Lead identification: literature (open & patent) nature (natural products) areful optimization of a lead structure via chemical synthesis methyl-ethyl-butyl-futile game umber of marketable drugs per compounds that undergo preliminary biological testing 0,000 ational drug design ombinatorial chemistry Peptides: poor bioavailability, poor transport, easily metabolized: poor drug candidates. owever, they are the natural substrates for many enzymes and receptors (drug targets) and have well-defined conformations: excellent lead compounds nzymes: converts a substrate to a distinct product eceptor: binds a ligand (no reaction), causing a chain of physiochemical events leading to a pharmacological response. gonist: substance that interacts (binds) with a receptor and elicits an observable response ntagonist: substances inhibits the affect of an agonist, but has no biological activity of its own

2 xample of molecular diversity: tetra-peptide: consider only the 0 natural amino acids (L-series) 0 = 0,000 different tetra-peptides! now include the -amino acids (0 L + = ) =. million different tetra-peptides!! now include 0 unnatural amino acids = million different tetra-peptides!!!! ombinatorial chemistry: method by which a family (library) of related compounds (structurally & synthetically) can be prepared and evaluated (screened) or multi-step synthesis, one must use solid-phase synthetic approach in order to expedite purification of intermediates Split synthesis (mixture libraries) combine, mix,split combine, mix,split

3 0 Split synthesis (con t) 0 Why not? eactivity of the coupling reaction may be different and this could bias the library Split synthesis approach, all compounds are equally represented (each coupling is individually controlled),,,,,, etc

4 econvolution of the library via biological activity and sub-library re-synthesis iological activity of the library select library - - iological activity of the library select library iological activity of the library select library Lead mpd

5 Problems: deconvolution of the library can be labor intensive can be fooled by low concentrations of highly active compounds activity is dependent upon the compound and its concentration activity observed is the the combined activity of the entire library dvantage: can synthesize a very large number of compounds very quickly and relatively easily depending on the chemistry. ncoded Libraries ) ) combine, mix,split ) ) combine, mix,split ) )

6 ncoded libaries (con t) leave the marker and analyze the code. ach unique marker codes for a unique peptide sequence ) ) ) ) ) ) : = = = = = = = = = ) linker- --M ) linker-code-- linker linker M code library ode (-0%) library region and coding region must be orthogonally protected ) piperidine ) add linker linker code M ) + )add code linker linker code ode M Synthesis of an encoded library

7 sub-library tag pool tag x y eading the code selectively remove the code from the resin hydrolyze and analyze + + n-ead ssay for eceptor inding using a luorescently Labeled eceptor ) dd labeled receptor labelled with fluorescent tag ) allow to bind to ligands on the beads ) wash to remove unbound receptor eads

8 Spatially ddressable, Parallel Synthesis 0 Spatially ddressable, Parallel Synthesis (con t)

9 Spatially addressable, parallel libraries dvantage: synthesizing pure compounds, no need to deconvolute the library isadvantage libraries tend to be much smaller iversomer apparatus cc. hem. es.,, -

10 nhibitors sp rg Val Tyr le is Pro Phe is Leu Val le is sn! angiotensinogen! inhibitors aspartyl protease renin sp rg Val Tyr le is Pro Phe is Leu! angiotensin! (little biological activity)! Zn + protease angiotensin converting enzyme () sp rg Val Tyr le is Pro Phe! angiotensin! (vasoconstriction high blood pressure)! iovan S aptopril Proteases: catalyzes the hydrolysis of peptide bonds protease +. Serine protease. ysteine protease. spartyl protease. Zinc (metallo) protease : zinc protease ( no x-ray or M structure), compared to carboxypeptidase or thermolysin important catalytic groups: lu-0, is-, is- (catalytic triad)

11 inhibitor Library r r g, t g r,-dipole g r Z,-diploar cycloaddition r = -, -, - ( ), - Ph Z l r Z r Z r = Z = tu S aptopril ( nhibitor) l = cs l cs l cs l 0 cmpds, each are multiple stereoisomers cs Ph K i ~ 0 pm (x better than aptopril Parallel Synthesis of a enzodiazepine Library ' M ' M ) ' ) + ) base ) X cleave from solid support ' ' enzodiazepine l l Valium (diazapam) Librium (chlordiazepoxide)

12 -aminobenzophenones Parallel Synthesis of a enzodiazepine Library α-amino acids alkylating agents - l r r (-aminobenzophenone) x (amino acids) x (alkyl halides) = compounds holecystikinin (K)! K-: sp-tyr(s)-met-ly-trp-met-sp-phe-! β-turn Mimics: (i+) (i+) (i+) (i) Linchpin Scaffold + β-turn + + S n( ) ( )n

13 ombinatorial synthesis of linchpin β-turn mimic r, T r S n S-tu S n S-tu ) M, T ) piperidine n S S-tu r, T n S S-tu r ) Ph P ) cyclization ) n S valuated for Somatostatin receptor binding! n=, x = x = 0 = β-turn mimics! 0