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DRUG DISCOVERY AND DEVELOPMENT “Synthesis analog compounds and Its Biological Activity ”

DRUG DISCOVERY AND DEVELOPMENT “Synthesis analog compounds and Its Biological Activity ”. MUHAMMAD HANAFI Research Centre forChemistry (RC Chem) - LIPI. INTRODUCTION. Hystory of Drug Discovery :.

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DRUG DISCOVERY AND DEVELOPMENT “Synthesis analog compounds and Its Biological Activity ”

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  1. DRUG DISCOVERY AND DEVELOPMENT “Synthesis analog compounds and Its Biological Activity” MUHAMMAD HANAFI Research Centre forChemistry (RC Chem) - LIPI

  2. INTRODUCTION Hystory of Drug Discovery : Isolation Salicin from bark Salix alba(bitterness) for analgesicdrug(Rev Edward Stone 1760), hydrolisis & oxidation (Raffaele Piria, 1838), acetylation of Salisylic acid (Charles Frederich Gerhardt, 1853), and finally pill form as 500 mg tablets in 1990) . Smith and Willis (1971) to prove that the blood-thinning properties (antiplatelets) Acetylsalicylic acid (aspirin) - less irritating - ester hydrolyzes to active drug

  3. Research Phases in Drug Development Target Identification And Validation Idea Search of Lead Structure Lead Structure Candidate for Development Product Optimization of Lead Structure Preclinical Development Development Product

  4. Four Main Approaches to Discovering New Drugs 1. From Natural Products : Screening to find biologically active component 2. From the drugs in use : Modification to improve activity or to find different 3. From synthetic chemicals and animal models Screening of chemical library by disease animal models 4. From the modern approach to drug design Designing drugs based on physiological mechanism

  5. DISCOVERY of NOVEL DRUGSfrom NATURAL PRODUCT Screening of Natural Compounds for Biological Activity : plants, microbes, marine, etc 2. Isolation and Purification of Active Principle 3. Determination of Structure : NMR, IR, MS 4. Structure-Activity relationships(SAR) : Identification of Pharmacophore 5. Synthesis of Analogues : Increase activity, reduce side effects 6. Receptor Theories : binding site information 7. Design and Synthesis of Novel Drug Structure

  6. Lead Compouns from Natural Products Lovastatin Aspergillus tereus Anticholesterol - Streptomycesp sp. 517-02 Cytotoxic to P338, KB Methyl cinnamte Calanone Callophyllum tesmanii Phenazine carbioxylate Pseudomonas pycocyaneae

  7. Time & Cost for A New Drug Development Compounds 5000-10000 250 5 1 drug Duration Costs (Mio US$) Research Preclinical Phase 3-6 yr 140 Development/ Clinical Phase Phase I Phase II Phase III 1.5 yr 30 2 yr 80 3.5 yr 330 Authority”s Assesment/NDA Phase 1.5 yr 60 11 – 15 yr ca. 750 Mio US$

  8. Drugs Fail Because of two Major Reason 39 % fail due to deficiencies in Absorption, Distribution, Metabolism & Elimination (ADME) 30% fail due to lack of efficacy 11% fail due to animal toxicity 10% fail due to adverse effects in man 5% fail due to commercial reason 5% miscellaneous

  9. Lipinski’s “Rule of Five” Christopher Lipinski proposed four parameters that define the "drug- likeness" of potential drug candidates based on analysis of existing drug molecules. "The Rule of Five" got its name from the cut-off values for each of these parameters of which all have values of five or a multiple of five. The “rule” states that poor absorption or permeation is more likely when : –A compound has > 5 H-bond donors (sum of OHs and NHs); –There are > 10 H-bond acceptors (sum of Ns and Os); –The MW is > 500; –TheLogP is > 5 (or MLogP is over 4.15). The “rule” is used by many as a useful guide in drug design.

  10. The rule of five - formulation Poor absorption or permeation are more likely when: • There are more than 5H-bond donors. • The molecular weight is over 500. • The LogP is over 5. • There are more than 10 H-bond acceptors.

  11. OPTIMAZATION ACTIVITY: Synthesis of DERIVATIVES/ Analogous

  12. Synthesis Derivative of Lead CompoundS

  13. Optimize Lead Compound

  14. Ester masking polar groups allowing passage through fatty cell membranes Esters as prodrugs Fatty barrier

  15. Amide: Carboxylic acid:

  16. Optimize Lead Compound Analogs of pharmacophore (remember morphine) Goals? 1. Variation of alkyl substituents 2. Variation of chain length

  17. Example: Adrenaline Salbutamol (Ventolin) (Anti-asthmatic) Propranolol (b-Blocker)

  18. Excess ring Excess functional groups Simplification

  19. DRUGS/LEAD COMPOUNDS DEVELOPMENTS

  20. Prodrug- Euquinine Euquinine is the esterification product of quinine with chloro-formic acid ethyl ester

  21. Synthesis of artemisini Derivatives Reduction NaBH4/EtOH Dihydroartemisinin Artemisinin Methyllation (MeI), Ethylation Artesunate

  22. Calanone derivatives and Its Cytotoxic Activity* Calanone Ester Calanol Calanol Log P 0.43 Against colon cancer cells HCT116: IC50 > 20 µg/mL L1210 : 59.4 µg/mL P388 : IC50 = 15 Log P -0.42 Against colon cancer cells HCT116: IC50 > 20 µg/mL L1210 : 70.0 µg/mL P388 : IC50 = 15 Log P 2.32 Against colon cancer cells HCT116: IC50 = 1.29 µg/mL P388 : IC50 = 7,5 µg/mL Cisplatin IC50 = 1.02 µg/ml *atent: M. Hanai, 2006

  23. PSMOE PSMOE DEVELOPMENT OF ANALOG UK-3A POTENTIAL FOR BREAST CANCER TREATMENT UK-3A Analog Development BcL-xL Protein PSMOE UK-3A Ring opening (Analog UK-3A)

  24. QSAR Parameter & Cytotoxic Test Results Log P -1.18 Ebinding = -7.1 kcal/mol IC50 = >100 mg/ml Log P 1.61 Ebinding = -11.65 kcal/mol P388 : IC50 = 38 mg/ml Log P 1.30, Ebinding = -10.24 kcal/mol KB :IC50 = 0.23 mg/ml YMB-1:IC50 = 0.015 mg/ml Log P 1.67 Ebinding = -10.39 kcal/mol

  25. Cytotoxic Test Results to P388, KB and YMB-1 Ebinding=-9.66 kcal/mol), Log P 1.5 IC50 34 mg/ml (P388) IC50 2.28 mg/ml (KB) IC50 1.83 mg/ml (YMB-1) Ebinding=-10.29 kcal/mol); Log P 1.62 IC50 38 mg/ml (P388) IC50 1.92 mg/ml (KB) IC50 5.46 mg/ml (YMB-1) Log P 2.09 P388 :IC50 = 40,0 mg/ml KB :IC50 = 0,82 mg/ml YMB-1:IC50 = 2,69 mg/ml

  26. Metabolite Secundar from Microbial Soil Pseudomonas pycocyanea dH15,5ppm p-Carboxyl-phenazine MIC 4,8 mg/ml (E. coli); 0,07 mg/ml ( S. aureus) IC50 : 5,20 mg/ml (L1210) Erythromycin : MIC 5,08 (E.coli), 4,06 (S. aureus) and 3,36 mg/ml (B. subtillis)

  27. SYNTHESIS Salycilanilide (SA)

  28. SALYCIL ANILIDE DERIVATIVES (PHENAZINES ANALOGS) Log P 3.29 Ebinding = -10.21 kcal/mol L1210: IC50 = 4.8 mg/ml P388 :IC50 = 7.75 mg/ml KB :IC50 = 0.6 mg/ml YMB-1:IC50 =2.97 mg/ml L1210 IC50 5,5 mg/ml L1210 IC50 7,0 mg/ml M. Hanafi, Paten P00200200449, 2002

  29. CYTOTOXIC ACTIVITY results Log P 3.29 P388 :IC50 = 7,55 mg/ml KB :IC50 = 0,78 mg/ml NOA : Log P 3,02 IC50 (T47D) : 4,67 mg/mL

  30. EFFICACY & TOXICITY TEST OF SALYCIL ANILIDE (SA) P388 :IC50 = 7.75 mg/ml KB :IC50 = 0.6 mg/ml YMB-1:IC50 =2.97 mg/ml • Acute Toxycity (LD50) : 365.83 mg/kg bw • and 429.46 mg/kg bw • Effective dose : 30 mg/kg bw a

  31. Synthesis Methyl Cinnamte derivatives 8-Methyl-4-phenylchroman-2-one 4-phenylchroman-2-one

  32. Cytotoxic Test to Leukemia Cell Line P388 Log P 2.2 Log P 1.93 Log P 3.85 Log P 3.86 Log P 3.36

  33. Find and Optimized a Lead Compound: Lovastatin »Minimise energy of structure : Chem3D, Gaussian, Mopac, » Structure Activy Correlationship : HyperChemPro » Direct Ligand Design (HMG-CoA rductase): Arguslab 4.0 » Synthesis » Bioaactivity Test

  34. Siynthesis Simvastatin from Lovastatin (1)* 2, 3, 4 1 Lovastatin R1 = TBDMSi or OCH2OMe 1. Protection :t-Bu(Me)2SiCl or (MeO)2CH2/P2O5 2. Hydrolysis (KOHaq or LiOH) 3. Cyclization, Heat/cyclohexane/pTsOH 4. Esterification : RCOCl, DMAP 5. Deprotection, TBAF/THF or PhSH 5 Simvastatin *US Patent, 6,506,929 B1, Jan. 14, 2003

  35. Synthesis Dehydrolovastatin (Lipistatin) 88,3 % (EtOH) H:EtOAc (4:1)

  36. INTERACTION ENERGY WITH HMG CoA REDUCTASE AND LOG P Interaction Dehydrolovastatin and the active site of HMG-CoA reductase

  37. Lipistatin Spectrum : 1H and 13C NMR

  38. Evaluation Results of Antihiperlipidemic Activity on Mice for Lipistatin and Simvastatin

  39. Comparative study on HDL-cholesterol raisingeffects of atorvastatin and dehydrolovastatin* * Marissa A Indah D. D, T. Yuliani, YAnita,L Meilawati, MJP, Andrianopsyah, and Hanafi, M. Journal of Applied Pharmaceutical Science 02 (03); 2012:

  40. Conclusion To get a new drug is very complex, take time, and costly Starting material (lead comp) could be isolated from the major comps. The Lipinski’s “Rule of Five is used by many as a useful guide in drug design. To optimized acrtivity of lead compouunds can be make derivatives, by simple methods: methylation. reduction, esterification, hydrolisis, and simplification Lipofilicity FG is important for biological activity Analog UK-3A were potential candidate anticancer Dehydrolovastatin is potential a new candidate drug for anticholesterol

  41. acknoledments • Indonesian Institute of Science (LIPI) & Ministry of Sci & Tech • (KNRT) and JSPS for fund • RC Chem LIPI for support facilities • Osaka City Univeristy Japan for cytotoxic test

  42. TERIMAKASIH

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