Bioisosterism. A Rational Approach in Drug Design. 刘俊辉 Sept. 30th Sila-majantol 1b. lily-of-the-valley flowers but more terpineol-like odor

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1 Bioisosterism A Rational Approach in Drug Design 刘俊辉 Sept. 30th 2005 Why is Bioisosterism? Me C 2 C Me Majantol 1a strong fresh-floral aqueousaldehydic, lily-of-the-valley flowers odor Me C 2 Si Me Sila-majantol 1b lily-of-the-valley flowers but more terpineol-like odor weak and not characteristic odor Me C 2 Ge Me Reinhold Tacke Germa-majantol 1c Syntheses, Structures, and Sensory Characteristics of the Perfume Ingredient Majantol and Its Analogs Sila-majantol and Germa-majantol: A Study on C/Si/Ge Bioisosterism Tacke, R. et al, rganometallics 2002, 21, 113.

2 CTETS 1. Introduction Brief of drug design process 2. Bioisosterism in Drug Design Evolvement of Bioisosterism Bioisosterism in Molecular Modification 3. Case Study From lead compound to dianilino-phthalimides Modeling Studies 4. Summary As the world s population grows older, functional and chronic diseases of advanced age have become a greater medical problem. Also, the increasing strains and stresses of modern life, with concentration of our population in large cities, faster and more dangerous means of locomotion, stiffer competition for professional opportunities, the threat of wars, and the uncertainties of the community in a socially unsettled world have raised the number of psychosomatic and mental disorders and their attendant physiological consequences to higher levels. Burger, A. Medicinal Chemistry, 3rd ed.; Wiley-Interscience: ew York, 1970

3 1. Introduction Brief of drug design process Figure 1. From Laboratory to Patient: The Complex Pathway of Biopharmaceutical R&D Pharmaceutical Industry Profile 2005 (Washington, DC: PhRMA, March 2005) Lead Compound Colchicine, a treatment for gout, was originally derived from the stem and seeds of the meadow saffron (autumn crocus). Illustration: ational Agriculture Library, ARS, USDA The lead compound is the starting point when designing a new drug. The compound should have some desirable property that is likely to be therapeutically useful. Pharmacodynamics The pharmacophore of a drug interacting with a molecular target including enzyme, protein, nucleic acid, lipid and carbohydrate in the body. Pharmacokinetics The study of what happens to a drug when it is administered to a patient. There are four main factors to be considered absorption, distribution, metabolism and excretion. 3

4 Traditional Drug Discovery Process Library *Screening* Data *Data analysis* Assay Further exploration Start Chemistry Drug Candidates Drug Candidates Figure 2. Phases of the drug discovery process Target identification Target validation Lead identification Lead optimization Preclinical and clinical development Cellular and molecular biology Genomics Proteomics Bioinformatics igh throughput screening atural Products screening MR-based screening Virtual screening Combinatorial chemistry Compound library design Structure-based design Knock-out animal models Antisense nucleic acids and antibodies Proteomics structural biology/structural genomics Medicinal chemistry Parallel synthesis Design of focused compound libraries Molecular modeling, QSAR Structure-based design in vivo pharmacology Pharmacokinetics and toxicology Modern Methods of Drug Discovery Birkhäuser Verlag: Switzerland, 2003

5 2. Bioisosterism in Drug Design Evolvement of Bioisosterism 1) Langmuir I. Compounds having the same number of atoms have also the same total number of electrons, the electrons may arrange themselves in the same manner. In this case the compounds or groups of atoms will be called isosteric compounds or isosteres. Table 1. Groups of Isosteres as Identified by Langmuir Irving Langmuir 2 and C 2 both acting as reversible anesthetics to the slime mold in 1948 Langmuir, I. J. Am. Chem. Soc. 1919, 41, ) Grimm s ydride Displacement Law Atoms anywhere up to four places in the periodic system before an inert gas change their properties by uniting with one to four hydrogen atoms, in such a manner that the resulting combinations behave like pseudoatoms, which are similar to elements in the groups one to four places respectively, to their right. Table 2. Grimm s ydride Displacement Law LaVoie, E. J. et al, Chem. Rev. 1996, 96, 3147.

6 3) Erlenmeyer. Isosteres as atoms, ions, and molecules in which the peripheral layers of electrons can be considered identical. Table 3. Isosteres Based on the umber of Peripheral Electrons LaVoie, E. J. et al, Chem. Rev. 1996, 96, ) Friedman. L. Bioisosteres were to include all atoms and molecules which fit the broadest definition for isosteres and have a similar type of biological activity, which may even be antagonistic. 5) Thornber C. W. LaVoie, E. J. et al, Chem. Rev. 1996, 96, Bioisosteres are groups or molecules which have chemical and physical similarities producing broadly similar biological activity. 6) Burger A. Thornber, C. W. Chem. Soc. Rev. 1979, 8, 563. Compounds or groups that possess near-equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical properties.... LaVoie, E. J. et al, Chem. Rev. 1996, 96, 3147.

7 Bioisosterism in Molecular Modification A chemical group can be mimicked by a similar group with similar biological activity another example of similarity a. Size b. Shape (bond angles, hybridization) c. Electronic distribution (Polarizability, inductive effects, charge, dipoles) e. Lipid solubility f. pk a g. Chemical reactivity (including likelihood of metabolism) h. ydrogen bonding capacity Database its Quantitative Structure-Activity Relationship (QSAR) Models Extract and Tabulate Descriptors Compound Activity (pk i ) "Y" Descriptors (X i ) Mol. Vol. (Å 3 ) LogP Dipole Mom (µ) etc. etc. etc. etc. etc.

8 Building QSAR Models (obs. property or activity) (molecular descriptors) Y = f(xi) Simple (Univariate) Linear Regression ammett, 1939 pk i = a o + a 1 (Mol Vol i ) ansch, 1969 Multiple Linear Regression (MLR) independent variable dependent pk variable i = a o + a 1 (Mol Vol best-fit i ) + a 2 constants (logp) + a 3 (µ i ) +... Partial Least-Squares (PLS) Regression Wold, et al pk i = a o + a 1 (PC1) + a 2 (PC2) + a 3 (PC3) +... Predicting Activities of Untested Compounds Using QSAR models as a predictive tool ew Lead: extract descriptors V logp µ Validated QSAR model: pk i = 0.52 (V i ) (logp i ) (µ i ) Predicted activity of new lead

9 Bioisosteres Classical Bioisosteres onlassical Bioisosteres Classical Bioisosteres 1. Monovalent Atoms or Groups 2. Divalent Isosteres 3. Trivalent Atoms or Groups 4. Tetrasubstituted Atoms 5. Ring Equivalents

10 a. F vs X F Antineoplastic van der Waal s radius (Å) DA Anti-inflammatory corticosteroid J. Med. Chem. 1994, 37,

11 b. 2,, S interchange J. Med. Chem. 1990, 33, c. Trivalent Atoms or Groups d. Tetrasubstituted Atoms J. Med. Chem. 1995, 38,

12 A Study on C/Si/Ge Bioisosterism Me C 2 C Me Me C 2 Si Me Majantol 1a strong fresh-floral aqueousaldehydic, lily-of-the-valley flowers odor Me C 2 Ge Me Sila-majantol 1b lily-of-the-valley flowers but more terpineol-like odor Reinhold Tacke Germa-majantol 1c weak and not characteristic odor Tacke, R. et al, rganometallics 2002, 21, 113. e. Ring Equivalents J. Med. Chem. 1994, 37,

13 onlassical Bioisosteres a. Cyclic vs oncyclic Replacement J. Med. Chem. 1989, 32, b. Replacements of Functional Groups ammett constant :σp Lipophilic value : π Relative size index: MR J. Med. Chem. 1974, 17,

14 3. Case Study From lead compound to dianilino-phthalimides 1. The lead compound Arcyriaflavin A PKC selective 3 C * * * 3 C * 3 C Staurosporine protein kinase inhibitor Bisindolyl-maleimides PKC selective Patrick, G. Instant otes in Medicinal Chemistry, BIS Scientific Publishers Ltd., UK, Dianilino-phthalimides Arcyriaflavin A Dianilino-Phthalimide (CGP 52411) EGF-receptor kinase inhibitor Relief of steric clash Steric clash Steric clash Twist Planar Propellor shape

15 3. Synthesis of dianilino-phthalimides TMSCl, Et3 DMF, 100 o C anilines Acetic acid, 120 o C R 1 2 C Si(C 3 ) 3 2 C Si(C 3 ) 3 3 C C 3 R 2 R 2 C 2 Me C 2 Me Toluene R 1 3 C C 3 ( 3 C) 3 Si Si(C 3 ) 3 a) Li, Me b) (Ac) 2, toluene R R 1 R 2 R 2 R 1 3 or formamides o C R 1 R 2 R 2 R 1 4. Drug metabolism of CGP Metabolism in man, mouse, rat and dog CGP (IC µM) Metabolism in monkey 5. Use of metabolic of blockers. Metabolic blocker F F Metabolic blocker CGP 53353

16 6. Chain extension CGP Ring expansion CGP (IC µM) Ring expansion Remove polar group CGP 57198(IC µM) CGP (IC µM) Modeling Studies BD BA (IC μM) Ar X Y X Cl Cl Chain contraction 2 EC µM X=, Y= EC μM X=, Y= EC μM Cl BD BA Chain extension X= EC μM X=Cl EC μM X=Me EC μM Cl X Ar X=Cl EC μM X=Me EC μM

17 4. Summary (i). The marketing of a drug has to be approved by regulatory authorities to ensure that the claims made for the product are accurate. (ii). ealth authorities across the world have attempted to cut the costs of medical health care by focusing on cheap generic drugs. There has been a steady decline in the number of drugs introduced each year into human therapy, from in the 1960s, in the 1970s, to about 50 in the 1980s and below 40 in the 1990s Thanks for your attention!

18 (i) Drug-like Behavior The Lipinski Rule of Five (1) Molecular Weight 500 (opt = ~350) ydrogen Bond Acceptors 10 (opt = ~5) ydrogen Bond Donors 5 (opt = ~2) -2 < clog P< 5 (opt = ~3.0) Rotatable Bonds 5 1: C. Lipinski et al, Adv. Drug. Del. Rev., 1997, 23, 3. Preclinical tests involving drug toxicology, pharmacology, formulation, stability and metabolism. Clinical : of or relating to the examination and treatment of patients and their illnesses. Clinical trials are carried out to test the therapeutic effects of new drugs and to ensure that they have no unacceptable side effects. There are four phases.

19 Types of Molecular Descriptors Constitutional, Topological 2-D structural formula * C 2 C 2 C 2 C 2 C C 2 * n C 2 Geometrical 3-D shape and structure Quantum Chemical Electrostatic Thermodynamic