Chemical Similarity and biological activities

Hugo Kubinyi, www.kubinyi.de Chemical Similarity and Biological Activities Hugo Kubinyi Germany E-Mail kubinyi@t-online.de HomePage www.kubinyi.de Hugo Kubinyi, www.kubinyi.de Similarity in Nature (Mimicry) Monarch, Danaus plexippus Hugo Kubinyi, www.kubinyi.de S MW = 78.11 mp. = 5.5°C bp. = 80.15°C Log P = 2.13 MR = 26.4 d = 0.879 MW = 84.14 mp. = -38°C bp. = 84°C Log P = 1.81 MR = 25.0 d = 1.057 1825, Michael Faraday "bicarburet of hydrogen", Fp. 42°F = 5.5°C 1879, Adolf v. Baeyer, Indigblau reaction 1882, Victor Meyer and Traugott Sandmeyer Discovery of thiophene The Serendipitous Discovery of Thiophene Hugo Kubinyi, www.kubinyi.de The Similarity Principle in Drug Design - Lead Optimization is an Evolutionary Procedure Medicinal chemists, all the time, used the similarity of chemical compounds to design new analogs of active leads. Whenever they discovered compounds with improved activity, selectivity, pharmacokinetics, etc., they used these compounds to search analogs with even further improved properties. However, ... Hugo Kubinyi, www.kubinyi.de Similarity and Diversity OOH OO ONH2 N CH3CH3 CH3CH2 N OO NH2NHNH2NH2 - +-+ Hugo Kubinyi, www.kubinyi.de Volumes and Surface Potentials Hugo Kubinyi, www.kubinyi.de Hydrophobic and Polar Regions Hugo Kubinyi, www.kubinyi.de Hydrogen Bond Donor Potentials Hugo Kubinyi, www.kubinyi.de Hydrogen Bond Acceptor Potentials Hugo Kubinyi, www.kubinyi.de Molecular Electrostatic Potentials (MEP) Hugo Kubinyi, www.kubinyi.de Selective Recognition of Theophylline by RNA N N N N O Me O Me R A theophyllin-binding aptamer binds theophylline (R = H) 10,000-times better than caffeine (R = Me) G. R. Zimmermann et al., Nat. Struct. Biol. 4, 644-649 (1997) IMB Jena Hugo Kubinyi, www.kubinyi.de NH2 CH3 CH3 COOH NH2 CH3 CH3 COOH NH2 CH3 CH3 COOH "valine pocket" "isoleucine pocket" NH2 CH3 COOH CH3 Recognition of Valine and Isoleucine A „suspicious“ check by isoleucine tRNA synthase rejects valines (1:200,000) but also 80% of all isoleucines. Correspondingly, the error rate is about 1:40,000. Hugo Kubinyi, www.kubinyi.de Lipophilicity and Blood-Brain Barrier N CH3 OH OH OH epinephrine a, dopamine, R = H b, L-Dopa, R = COOH N CH3 CH3 OH NH2 CH3 N CH3 O O CH3 ephedrine amphetamine (speed) MDMA (Ecstasy, XTC) H H H OH OH R NH2 Polar Compounds Lipophilic Compounds Intermediate Lipophilicity Hugo Kubinyi, www.kubinyi.de Agonists and Antagonists OH NOH OH R OH Cl Cl N CH3 CH3 H H R = H , norepinephrine R = CH3, epinephrine R = CH(CH3)2, isoproterenol dichloroisoproterenol, DCI O OH OH N R H morphine R = CH3 (agonist) nalorphine R = CH2-CH=CH2 (antagonist) Hugo Kubinyi, www.kubinyi.de Agonists and Antagonists N N NH2 H O N CH3 CH3 O O N Et Et histamine (agonist) diphenhydramine (antagonist) acetylcholine (agonist) drofenine (antagonist) CH3 O O N CH3 CH3 CH3+ Hugo Kubinyi, www.kubinyi.de OH OH NH2 N H H t-Bu OH (+)-butaclamol (antagonist) dopamine (agonist) OH OH N CH3H apomorphine (agonist) Agonists and Antagonists Hugo Kubinyi, www.kubinyi.de Unexpected Effects of Alkyl Group Variation N N N S N O R CH3 CH3 O O CH3 H R = H (antagonist) IC50-AT1 = 0.3 nM IC50-AT2 = 4 500 nM R = CH2CH(CH3)2 (agonist) IC50-AT1 = 13 nM IC50-AT2 = 10 nM N N N S N O OBu CH3 CH3 O O CH3 R H L 162,389 R = H (antagonist) IC50-AT1 = 4.0 nM L 162,782 R = CH3 (agonist) IC50-AT1 = 25 nM Hugo Kubinyi, www.kubinyi.de N N N H OO ON O R N H R = H, Me CCK-A antagonists R = Et, Pr, i-Pr CCK-A agonists N R O Cl Cl N O N H O O N H R = H bradykinin B2 antagonist R = bradykinin B2 agonistO CH2 N Unexpected Effects of Alkyl Group Variation N. R. A. Beeley, Drug Discov. today 5, 354-363 (2000) Hugo Kubinyi, www.kubinyi.de Substituents: F, Cl, Br, I, CF3 , NO2 Methyl, Ethyl, Isopropyl, Cyclopropyl, t.-Butyl, -OH, -SH, -NH2 , -OMe, -N(Me)2 Linkers: -CH2-, -NH-, -O- -COCH2-, -CONH-, -COO- >C=O, >C=S, >C=NH, >C=NOH, >C=NOAlkyl Atoms and Groups in Rings: -CH=, -N= -CH2-, -NH-, -O-, -S-, -CH2CH2-, -CH2-O-, -CH=CH-, -CH=N- Large Groups: -NHCOCH3, -SO2CH3 -COOH, -CONHOH, -SO2NH2, OH OH N N N OH HH N NH N N , O N NH O Isosteric Replacement of Atoms and Groups Hugo Kubinyi, www.kubinyi.de Consequences of Isosteric Replacement O CH2CH(NH2)COOHOH Y X XZ COOH X CH3 ONH2 R a, X = Y = I, Z = H, triiodothyronine, T3 b, X = Y = Z = I, thyroxine, T4 c, X = I, Y = i-propyl, Z = H d, X = CH3, Y = i-propyl, Z = H p-aminobenzoic acid, R = COOH sulfanilamide, R = SO2NH2 X = -O- acetylsalicylic acid Hugo Kubinyi, www.kubinyi.de Consequences of Isosteric Replacement Inhibition of Carbonic Anhydrase by Sulfonamides Specificity of GABA Receptor Ligands NH2 OH O GABA NH2 P OH O H GABAA GABAB receptor affinity IC50 = 20 nM 20 nM IC50 = 4,500 nM 1 nM CH3SO2NH2, Ki = 100 µµµµM, pKa = 10.5 CF3SO2NH2, Ki = 2 nM, pKa = 5.8 Hugo Kubinyi, www.kubinyi.de TRß1-Selective Thyromimetics Have No Cardiotoxic Side Effects O NHC(=O)COOHOH Me Me Me Me CH2 OCH2COOHOH Me Me Me Me T3 TRαααα > TRß CGS-23425 (Ciba-Geigy) TRαααα < TRß GC-1 (UCSF) TRαααα < TRß T. S. Scanlan et al., Curr. Opin. Drug Disc. Dev. 4, 614-622 (2001) Hugo Kubinyi, www.kubinyi.de A Diisopropyl,dibromo Analog of T4 Acts as Thyroid Hormone Receptor Antagonist OOH Br Br Me Me Me Me COOH J. D. Baxter et al., Endocrinology 143, 517-524 (2002) TRαααα no agonistic activity TRß weak partial agonist blocks T3 and T4 binding to the thyroid hormone receptor Hugo Kubinyi, www.kubinyi.de A Neutral TRß-Selective Thyromimetic Binds to a TRß R320C Mutant CH2 CH2CH2-OHOH Me Me Me Me CH2 OCH2COOHOH Me Me Me Me activity in nM TRαααα TRß TRß wild type mutant T3 0.14 0.66 4.3 GC-1 6.6 3.7 38 HY1 38 32 7.0 H. F. Ye et al., J. Am. Chem. Soc. 123, 1521-1522 (2001) Hugo Kubinyi, www.kubinyi.de Isosteric Replacement of Aromatic Rings N N naftifine terbinafine NH2OH OH a strong dopamine D3 agonist dopamine H N(Prop)2 A. Stütz, Angew. Chem. Int. H. Hübner et al., J. Med. Ed. Engl. 26, 320-328 (1987) Chem. 43, 756-762 (2000) Hugo Kubinyi, www.kubinyi.de Isosteric Replacement in Corticotropin-Releasing Factor-1 (CRF1) Receptor Antagonists N N N NH N Me Me Me N N NH N Cl Cl Cl N N NH N Cl Cl Cl N N NH N Cl Cl Cl N N NH N Cl Cl Cl Ki CRF1 = 57 nM 70 nM 30 nM 2 nM >10,000 nM C. Chen et al., J. Med. Chem. 39, 4358-4360 (1996) Hugo Kubinyi, www.kubinyi.de SAR of Epibatidine and its Structural Analogs (displacement of cytisine at neuronal nACh receptors) NH N Cl H (±)-epibatidine Ki = 0.043 nM N H N O R R = N H N Me N Me Ki = 0.16 nM 0.15 nM 0.052 nM 0.45 nM N H N H N Me N Me Ki = 0.14 nM 19.7 nM 0.05 nM 3.5 nM cf. nicotine Ki = 1 nM N N CH3 H (S) series (R) series M. A. Abreo et al., J. Med. Chem. 39, 817-835 (1996) Hugo Kubinyi, www.kubinyi.de SAR of Epibatidine and its Structural Analogs (affinity to the αααα2ββββ4 nACh receptor) NH N Cl H NH N Cl H (+)-epibatidine Ki = 19 pM (-)-epibatidine Ki = 20 pM (±)-homoepibatidine Ki = 230 pM (±)-5-exo-aryl-aza- bicycloheptane inactive (±)-5-endo-aryl-aza- bicycloheptane Ki = 56 pM NH N Cl H NH N Cl H (±)-6-exo-aryl-aza- bicycloheptane inactive (±)-6-endo-aryl-aza- bicycloheptane Ki = 45 pM NH N Cl H NH N Cl H C. D. Cox et al., J. Chem. Soc. Perkin Trans. 1, 2001 (19), 2372-2379 Hugo Kubinyi, www.kubinyi.de Binding Modes of Steroids to an Antibody P. Wallimann, T. Marti, A. Fürer and F. Diederich, Steroids in Molecular Recognition, Chem. Rev. 97, 1567-1608 (1997) a) progesterone b) unliganded antibody c) aetiocholanolone (A/B cis) Hugo Kubinyi, www.kubinyi.de Cytochrome P450 Inhibitors N CH3 CH3 O N N NH N N N NH Metyrapone 1-Phenyl- imidazole 4-Phenyl- imidazole 2-Phenyl- imidazole 2.2.10-9 M1.0.10-7 M 4.0.10-5 M 7.0.10-6 M T. L. Poulos and A. J. Howard, Biochemistry 26, 8165-8174 (1987) Hugo Kubinyi, www.kubinyi.de Hugo Kubinyi, www.kubinyi.de Hugo Kubinyi, www.kubinyi.de Hugo Kubinyi, www.kubinyi.de Hugo Kubinyi, www.kubinyi.de A Giant Stag-Beetle (organic matter) and a Marine Snail (anor- ganic matter?) Hugo Kubinyi, www.kubinyi.de Right or Left ? Conus nicoba- ricus (Natural History Museum, London) Hugo Kubinyi, www.kubinyi.de Museo de Ciencias Naturales, Buenos Aires, Argentina Busycon coarctatum Busycon contrarium Hugo Kubinyi, www.kubinyi.de Biological Effects of Enantiomers CH3 CH3 CH3 O CH3 O (R)-(+)- (S)-(-)- (S)-(+)- (R)-(-)- Limonene Carvone odor: orange lemon caraway peppermint NH2 O NH2 COOH NH2 O NH2 COOH L-Asn D-Asn taste: bitter sweet CHO OH OMe CHO OH OMe strong odor isovanillin no odor vanillin cf. Hugo Kubinyi, www.kubinyi.de Odor Threshold Values of Isomeric Wine Lactones O CH3 OCH3 O CH3 OCH3 O CH3 OCH3 O CH3 OCH3 0.00002 ng/l > 1,000 ng/l 0.25 ng/l 120 ng/l O CH3 OCH3 O CH3 OCH3 O CH3 OCH3 O CH3 OCH3 0.01 ng/l 20 ng/l 0.1 ng/l 12 ng/l 3S,3aS,7aR 3R,3aR,7aS 3R,3aS,7aR 3S,3aR,7aS 3S,3aS,7aS 3R,3aR,7aR 3S,3aR,7aR 3R,3aS,7aS 3a 4 5 6 7 7a 3 Hugo Kubinyi, www.kubinyi.de N H H t-Bu OH Eudismic ratio = affinity ratio of (+)- and (-)-enantiomers αααα1 receptor 73 D2 receptor 1 250 r-HT1 receptor 8 5-HT2 receptor 73 muscarinic ACh receptor 0.5 (+)-Butaclamol Biological Activities of Enantiomers Hugo Kubinyi, www.kubinyi.de all drugs 100% synthetic achiral chiral race- mates 1% achiral or racemate 72% 62% 38% 88% 99% one enantiomer natural products 28% 12% one enantiomer Kleemann and Engel, 1988 Chiral and Achiral Drugs chiral switch Hugo Kubinyi, www.kubinyi.de Percentage of achiral drugs, single enantiomers and racemates Chiral and Achiral Drugs, 1983-2002 H. Caner et al., Drug Discov. today 9, 105-110 (2004) Hugo Kubinyi, www.kubinyi.de N N O O O CH3 CH3 * OCOEt H N CH3 CH3CH3 * * N-methyl-phenyl- propylbarbiturate propoxyphen N O N OO O* thalidomide H H CH3 N CN CH3 CH3 NH R metabolic degradation* * R = CH3 or R = H COOH H CH3 CH3 CH3 * (R)-(-) form COOH CH3 H CH3 CH3 * no inversion (S)-(+) form metabolic inversion MAO inhibitor ibuprofen Biological Activities of Enantiomers Hugo Kubinyi, www.kubinyi.de Biological Activities of Diastereomers NH2 O OH OH N CH3 * * Labetalol (E. J. Ariens: "A racemate is a compound containing 50% impurity") R1 N R2 OHH H CH3 R1 N R2 HOH CH3 H R1 N R2 OHH CH3 H R1 N R2 HOH H CH3 (R,R) (R,S)(S,S) (S,R) H H HH H pA2 values R,R S,S R,S S,R a1 rezeptor 5.87 5.98 5.50 7.18 ß1 receptor 8.26 6.43 6.97 6.37 ß2 receptor 8.52 <6.0 6.33 <6.0 Hugo Kubinyi, www.kubinyi.de Enantiomers as Agonists and Antagonists N CF3 CH3 CH3 H H O2N COOMe (S)-(-) form: agonist (R)-(+) form: weak antagonist Bay k 8644 O N O NH N O COOH F H H R,S diastereomer: CCK1 agonist S,R diastereomer: CCK1 antagonist Hugo Kubinyi, www.kubinyi.de Me Me Me N NH Medetomidine * Enantiomers as αααα2A Agonists and Inverse Agonists (influence on intracellular Ca2+ concentration) C.C. Jansson et al., Mol. Pharmacol. 53, 963-968 (1998) Hugo Kubinyi, www.kubinyi.de tipranavir (PNU 140 690) OO NH NS O O OH CF3 6 3a Diastereo- Ki IC50 IC90 mer pM µM µM R,R 8 0.03 0.10 R,S 18 0.14 0.84 S,R 32 0.41 1.8 S,S 220 1.7 3.0 S. R. Turner et al., J. Med. Chem. 41, 3467-3476 (1998) Comparable Activities of Diastereomers Hugo Kubinyi, www.kubinyi.de Losartan Binding to the Angiotensin II Receptor N N Cl OH NH NN N Losartan Saralasin = [Sar1,Ala8]Angiotensin II The rat AT1a receptor binds Angiotensin II, Saralasin and Losartan with nanomolar affinities. The frog ATa receptor (from Xenopus laevis) binds only Angiotensin II and Saralasin. The amino acids involved in Losartan binding are in the TM helices II - VII. There is a 95% amino acid homology among mammalian receptors, but only about 60% homology to avian and amphibian receptors. Hugo Kubinyi, www.kubinyi.de Losartan Binding: From Frogs to Rats (H. Ji et al., Proc. Natl. Acad. Sci. USA 92, 9240-44 (1995)) Saralasin Losartan binding binding Rat rAT1b receptor 1.7 nM 2.2 nM Frog xATa receptor 19 nM >50,000 nM Rat rAT1b receptor mutant 14 nM >50,000 nM A73S, V108I, S109I, A163S, P192M, T198A, F248L, S252C, L300F, F301L Frog xATa receptor mutant 16 nM 2.0 nM S74A, I109V, T110S, T115A, T116S, S164A, M193P, A199T, L247F, C251S, S294N, F299L, L300F Hugo Kubinyi, www.kubinyi.de 5-HT1B Receptor Ligands: From Humans to Rats E. M. Parker et al., J. Neurochem. 60, 380-383 (1993) Compound Rat Human wild type Thr355Asn 5-Hydroxytryptamine (5-HT) 5-Carboxamidotryptamine (5-CT) Sumatriptan N,N-Dipropyl-5-CT 5-Methoxy-N,N-dimethyltryptamine Methysergide Metergoline Rauwolscine (-)-Propranolol (+)-Pindolol 0.016 0.007 0.47 >10 3.6 1.8 0.13 6.3 0.06 0.15 0.03 0.003 0.11 0.41 0.15 0.34 0.03 0.28 10.9 24.3 0.012 0.002 0.64 9.7 1.7 2.8 0.15 13.2 0.013 0.05 Log Ki (Rat) vs. log Ki (Human) r ≈≈≈≈ 0.27 r ≈≈≈≈ 0.98 Hugo Kubinyi, www.kubinyi.de 5-HT1B Receptor Ligands: From Humans to Rats Hugo Kubinyi, www.kubinyi.de N NNH2 NH2 OMe OMe OMe (positively charged form at pH = 7.4) + H DHFR from KD in nM E. coli E. coli, Gln 118 mutant E. coli, Arg 28, Gln 118 mutant L. casei N. gonorrhoeae Chicken, Mouse Cattle Man 0.02 0.09 3.8 0.4 15 3 500 330 1 000 Trimethoprim vs. Different Species and Mutants Hugo Kubinyi, www.kubinyi.de DHFR Pro Ala Pro Cys His E. coli TRIMETHOPRIM (positive charge) Glu Asp Met Leu Chicken TRIMETHOPRIM (positive charge) Lys Lys Arg Lys Arg Leu E. coli wild type TRIMETHOPRIM (positive charge) Glu Gln E. coli mutants TRIMETHOPRIM (positive charge) Arg Hugo Kubinyi, www.kubinyi.de Hugo Kubinyi, www.kubinyi.de References H. Kubinyi, Chemical Similarity - A Medicinal Chemist‘s View, Erlanger Historical Lectures, 07.03.2002 (see www.chemie.uni- erlangen.de/clark/multimedialabor/_lectures/online_drug_design/ lecture_02/index.html). H.-J. Böhm, G. Klebe and H. Kubinyi, Wirkstoffdesign, Spektrum Akademischer Verlag, Heidelberg, 1996. P. M. Dean, Ed., Molecular Similarity in Drug Design, Blackie Academic & Professional, London, 1995. H. Kubinyi, Similarity and dissimilarity: a medicinal chemist’s view, in 3D QSAR in Drug Design. Ligand-Protein Interactions and Molecular Similarity, H. Kubinyi, G. Folkers and Y. C. Martin, Eds. Kluwer Academic Publishers, Dordrecht, 1998, S. 225-252; also published in Persp. Drug Discov. Design 9-11, 225-252 (1998). G. A. Patani and E. J. LaVoie, Bioisosterism: A rational approach in drug design, Chem. Rev. 96, 3147-3176 (1996). A. Burger, Isosterism and bioisosterism in drug design, Prog. Drug. Res. 37, 287-371 (1991).