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Discovery of Small Peptides and Peptidomimetics Targeting The Till Olof List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Fransson, R., Botros, M., Nyberg, F., Lindeberg, G., Sandström, A., Hallberg, M. Small Peptides Mimicking Substance P (1–7) and Encompassing a C-terminal Amide Functionality. Neuropeptides. 2008, 42, 31–37. II Fransson, R., Botros, M., Sköld, C., Nyberg, F., Lindeberg, G., Hallberg, M., Sandström, A. Discovery of Dipeptides with High Affinity to the Specific Binding Site for Substance P 1–7. J. Med. Chem. 2010, 53, 2383-2389. III Fransson, R., Botros, M., Sköld, C., Kratz, J. M., Svensson, R., Artursson, P., Nyberg, F., Hallberg, M., Sandström, A. Con- strained H-Phe-Phe-NH2 Analogues with High Affinity to the Substance P 1–7 Binding Site and with Improved Metabolic Stability and Cell Permeability. Manuscript. IV Fransson, R., Nordvall, G., Botros, M., Carlsson, A., Kratz, J. M., Svensson, R., Artursson, P., Nyberg, F., Hallberg, M., Sandström, A. Discovery and Pharmacokinetic Profiling of Phenylalanine Based Carbamates as Novel Substance P 1–7 Analogues. Manuscript. V Fransson, R., Sköld, C., Bitar, M., Larhed, M., Sandström, A. Design and Synthesis of N-Terminal Imidazole-Based H-Phe- Phe-NH2 Mimetics. Manuscript. VI Wi ckowska, A., Fransson, R., Odell, L. R., Larhed, M. Mi- crowave-Assisted Synthesis of Weinreb and MAP Aryl Amides via Pd-Catalyzed Heck Aminocarbonylation Using Mo(CO)6 or W(CO)6. J. Org. Chem. 2011. 76, 978-981. Reprints were made with the permission of the respective publishers. Contents 1. Introduction ............................................................................................... 11 1.1 Neuropeptides ..................................................................................... 11 1.2 Peptides as Drug Leads ...................................................................... 12 1.3 Strategy for the Development of Peptidomimetics ............................ 13 1.4 Property-Based Design ....................................................................... 15 2. The Substance P System ........................................................................... 19 2.1 Substance P and its Bioactive Metabolites ......................................... 19 2.2 SP1–7 and its Binding Site ................................................................... 21 2.2.1 Endomorphins ............................................................................. 23 3. Aims .......................................................................................................... 25 4. SAR and Truncation Studies of SP1–7 and EM-2 ...................................... 26 4.1 Background and Strategy ................................................................... 26 4.2 Solid-Phase Peptide Synthesis ............................................................ 27 4.3 Synthesis of SP1–7 Analogs ................................................................. 29 4.4 Biological Evaluation ......................................................................... 30 4.4.1 Structure–activity relationship .................................................... 30 4.4.2 Effects of SP1–7 and its analogs ................................................... 37 4.5 Chapter Summary ............................................................................... 38 5. Design and Synthesis of Small Constrained H-Phe-Phe-NH2 Analogs .... 39 5.1 Background and Strategy ................................................................... 39 5.2 Biological Evaluation ......................................................................... 40 5.2.1 Structure–activity relationship and ADME properties ............... 40 5.3 Chapter Summary ............................................................................... 48 6. Improvement of the Pharmacokinetic Profile of Substance P1–7 Ligands . 49 6.1 Background and Strategy ................................................................... 49 6.2 Synthesis of Phenylalanine-Based Carbamates .................................. 50 6.3 Biological Evaluation ......................................................................... 51 6.3.1 Structure–activity relationship and ADME properties ............... 51 6.4 Chapter Summary ............................................................................... 55 7. Microwave-Assisted Aminocarbonylations and Direct Arylation of Imidazoles. Application to MAP Amides and SP1–7 Analogs ....................... 56 7.1 Background ........................................................................................ 58 7.1.1 Microwave irradiation in organic synthesis ................................ 58 7.1.2 Palladium-catalyzed reactions .................................................... 58 7.1.3 Design of experiments ................................................................ 61 7.2 Method Development ......................................................................... 62 7.2.1 Microwave-assisted protocol for C5 arylation of imidazole ....... 62 7.2.2 Microwave-assisted aminocarbonylation using CO-gas-free conditions ............................................................................................. 64 7.3 Application of the Developed Methods in the Synthesis of H-Phe-Phe- NH2 Mimetics ........................................................................................... 70 7.4 Chapter Summary ............................................................................... 72 8. Concluding Remarks ................................................................................. 73 Acknowledgements ....................................................................................... 75 References ..................................................................................................... 78 Abbreviations Ac acetyl ACE the angiotensin-converting enzyme ADME absorption, distribution, metabolism and excretion Ala alanine Arg arginine Asp aspartic acid BBB blood-brain barrier Boc tert-butoxycarbonyl CDI 1,1´-carbonyldiimidazole Cha cyclohexylalanine Chg cyclohexylglycine CHO-K1 Chinese hamster ovary cell line CMD concerted metalation–deprotonation CNS central nervous system DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DIEA N, N-diisopropylethylamine DMAP N, N-dimethylaminopyridine DMF N, N-dimethylformamide DMSO dimethylsulfoxide DP-IV the post-proline dipeptidyl peptidase Fmoc 9-fluorenylmethoxycarbonyl EM-1 endomorphin-1 EM-2 endomorphin-2 FHDoE focused hierarchical design of experiments GI gastrointestinal tract Gln glutamine Gly glycine HATU N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridine-1- yl-methylene]-N-methylmethanaminium hexafluorophos- phate N-oxide HBTU N-[(1H-benzotriazole-1-yl)-(dimethylamino)methylene]-N- methylmethanaminium hexafluorophosphate N-oxide HPLC high-performance liquid chromatography IC50 inhibitor concentration giving 50% inhibition Ki equilibrium dissociation constant for inhibitor binding Leu leucine Lys lysine MAP N-methyl-amino pyridyl NEP the neutral endopeptidase NK neurokinin NMM N-methylmorpholine NMR nuclear magnetic resonance Pbf 2,2,4,6,7-pentamethyldihydrobenzofuran-5-yl-sulfonyl PepT1 di/tri-peptide transporter PgP P-glycoprotein Phe phenylalanine PK pharmacokinetics PPB plasma protein binding PPCE the post-proline-cleaving enzyme Pro proline PSA polar surface area SAR structure–activity relationship SEM standard error of mean SP substance P SP1–7 substance P 1–7 SPE the substance P endopeptidase SPPS solid-phase peptide synthesis Suc succinoyl TES triethylsilane TFA trifluoroacetic acid Trp tryptophan Trt triphenylmethyl Tyr tyrosine Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene 1. Introduction 1.1 Neuropeptides The classical neurotransmitters in the nervous system are amino acids and their metabolites (glutamate, aspartate, GABA and glycine), the monoamines (acetylcholine, dopamine, noradrenaline and serotonin), and “gaseous” molecules (nitric oxide and carbon monoxide). In addition to these, neuro- peptides also function as messengers. The neuropeptides often co-exist in the neurons, together with other neurotransmitters, functioning in a complemen- tary way by modulating their actions. These neurotransmitters and/or neuro- modulators constitute a large and significant group of biologically active peptides.1-3 Neuropeptides are present in all parts of the nervous system, but each has its unique distribution pattern. Thus, neuropeptides can be expressed at high levels under normal conditions and be available at any time, or they can normally be expressed at low concentrations and become up-regulated as a result of, for example, nerve injury, stress or drug abuse. It should be noted that the expression pattern of a specific neuropeptide may vary depending on the neuron in which it is expressed and the role it plays there; a specific peptide can thus exhibit different expression patterns.1 This observed modulating role of neuropeptides on the main transmitters, e.g. monoamines, is interesting from a therapeutic point of view, and targeting the functions of the neuropeptides instead of the classical neurotransmitters can be of advantage in drug development. Firstly, the “milder” effects observed for neuropeptides compared to monoamines and amino acid transmitters result in less dramatic activation or blockade effects on their receptors.1,2 Secondly, since the neuropeptides are often released from neurons under pathological conditions, antagonists may have no effect in “normal systems” but act only on unbalanced systems
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