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Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors

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Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 197 Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors Targeting Different Genotypes and Drug-Resistant Variants ANNA KARIN BELFRAGE ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6192 ISBN 978-91-554-9166-6 UPPSALA urn:nbn:se:uu:diva-243317 2015 Dissertation presented at Uppsala University to be publicly examined in B41 BMC, Husargatan 3, Uppsala, Friday, 27 March 2015 at 09:15 for the degree of Doctor of Philosophy (Faculty of Pharmacy). The examination will be conducted in Swedish. Faculty examiner: Ulf Ellervik (Lunds tekniska högskola). Abstract Belfrage, A. K. 2015. Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors. Targeting Different Genotypes and Drug-Resistant Variants. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 197. 108 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9166-6. Since the first approved hepatitis C virus (HCV) NS3 protease inhibitors in 2011, numerous direct acting antivirals (DAAs) have reached late stages of clinical trials. Today, several combination therapies, based on different DAAs, with or without the need of pegylated interferon-α injection, are available for chronic HCV infections. The chemical foundation of the approved and late-stage HCV NS3 protease inhibitors is markedly similar. This could partly explain the cross-resistance that have emerged under the pressure of NS3 protease inhibitors. The first-generation NS3 protease inhibitors were developed to efficiently inhibit genotype 1 of the virus and were less potent against other genotypes. The main focus in this thesis was to design and synthesize a new class of 2(1H)-pyrazinone based HCV NS3 protease inhibitors, structurally dissimilar to the inhibitors evaluated in clinical trials or approved, potentially with a unique resistance profile and with a broad genotypic coverage. Successive modifications were performed around the pyrazinone core structure to clarify the structure-activity relationship; a P3 urea capping group was found valuable for inhibitory potency, as were elongated R6 residues possibly directed towards the S2 pocket. Dissimilar to previously developed inhibitors, the P1’ aryl acyl sulfonamide was not essential for inhibition as shown by equally good inhibitory potency for P1’ truncated inhibitors. In vitro pharmacokinetic (PK) evaluations disclosed a marked influence from the R6 moiety on the overall drug-properties and biochemical evaluation of the inhibitors against drug resistant enzyme variants showed retained inhibitory potency as compared to the wild-type enzyme. Initial evaluation against genotype 3a displayed micro-molar potencies. Lead optimization, with respect to improved PK properties, were also performed on an advanced class of HCV NS3 protease inhibitors, containing a P2 quinazoline substituent in combination with a macro-cyclic proline urea scaffold with nano-molar cell based activities. Moreover, an efficient Pd-catalyzed C-N urea arylation protocol, enabling high yielding introductions of advanced urea substituents to the C3 position of the pyrazinone, and a Pd- catalyzed carbonylation procedure, to obtain acyl sulfinamides, were developed. These methods can be generally applicable in the synthesis of bioactive compounds containing peptidomimetic scaffolds and carboxylic acid bioisosteres. Keywords: hepatitis C virus, HCV, NS3 protease inhibitors, structure-activity relationship, 2(1H)-pyrazinone, quinazoline, resistance, Pd catalysis Anna Karin Belfrage, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Box 574, Uppsala University, SE-75123 Uppsala, Sweden. © Anna Karin Belfrage 2015 ISSN 1651-6192 ISBN 978-91-554-9166-6 urn:nbn:se:uu:diva-243317 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-243317) Till Johan och Hedda ♥ List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Nilsson, M., Belfrage, A K., Lindström, S., Wähling, H., Lindquist, C., Ayesa, S., Kahnberg, P., Pelcman, M., Benkestock, K., Agback, T., Vrang, L., Terelius, Y., Wikström, K., Hamelink, E., Rydergård, C., Edlund, M., Eneroth, A., Ra- boisson, P., Lin, T-I., de Kock, H., Wigerinck, P., Simmen, K., Samuelsson, B., Rosenquist, Å.* Synthesis and SAR of potent inhibitors of the hepatitis C virus NS3/4A protease: Exploration of P2 quinazoline substituents. Bioorg. Med. Chem. Lett., 2010, 20, 4004-4011. II Gising, J.,# Belfrage, A K.,# Alogheli, H., Ehrenberg, A., Åkerblom, E., Svensson, R., Artursson, P., Karlén, A., Dan- ielson, U. H., Larhed, M., Sandström, A.* Achiral pyrazinone- based inhibitors of the hepatitis C virus NS3 protease and drug- resistant variants with elongated substituents directed toward the S2 pocket. J. Med. Chem., 2014, 57, 1790-1801. III Belfrage, A K., Abdurakhmanov, E., Åkerblom, E., Oshalim, A., Gising, J., Skogh, A., Danielson, U. H., Sandström, A. Py- razinone based hepatitis C virus NS3 protease inhibitors target- ing genotypes 1a and 3a, and the drug-resistant enzyme variant R155K. Manuscript. IV Belfrage, A K.,* Gising, J., Svensson, F., Åkerblom, E., Sköld, C., Sandström, A. Efficient and selective palladium-catalysed C3-urea couplings to 3,5-dichloro-2(1H)-pyrazinones. EurJOC., 2015, 978-986. V Belfrage, A K., Wakchaure, P., Larhed, M., Sandström, A. Pal- ladium-catalyzed carbonylation of aryl iodides with sulfin- amides. Manuscript. *Corresponding author. # These authors contributed equally. Reprints were made with permission from the respective publishers. Contents 1 Introduction .............................................................................................. 11 1.1 Hepatitis C Virus ............................................................................. 11 1.1.1 General Background .............................................................. 11 1.1.2 Course and Outcome of HCV Infection ................................. 12 1.1.3 The Viral Life Cycle .............................................................. 13 1.1.4 The Viral Proteins .................................................................. 15 1.2 Treatment Strategies ....................................................................... 15 1.2.1 Current Treatment .................................................................. 16 1.3 Resistance to Direct Acting Antiviral Drugs .................................. 19 1.4 HCV NS3 Protease .......................................................................... 21 1.5 Discovery and Development of HCV NS3 Protease Inhibitors ...... 24 1.5.1 A Historical View of the Discovery of HCV NS3 Protease Inhibitors ................................................................................ 25 1.6 Model Systems for Analyzing HCV NS3 Protease Inhibitors ........ 28 2 Aims of the Thesis ................................................................................... 32 3 P2 Quinazoline Substituents in HCV NS3 Protease Inhibitors (Paper I) .................................................................................................... 33 3.1 Pharmacokinetic Aspects in Drug Discovery ................................. 33 3.2 Harmonizing Antiviral Potency with PK Properties in the Development of HCV NS3 Protease Inhibitors (Paper I) ............... 34 3.3 Synthesis of P2 Quinazoline-Containing HCV NS3 Protease Inhibitors ......................................................................................... 39 4 2(1H)-Pyrazinone-Based HCV NS3 Protease Inhibitors (Papers II and III) ..................................................................................... 45 4.1 Pyrazinones in Medicinal Chemistry .............................................. 45 4.2 From Tripeptides to Pyrazinone-Based HCV NS3 Protease Inhibitors ......................................................................................... 46 4.3 Development of Achiral Inhibitors (Paper II) ................................. 46 4.4 Exploration of the P1P1’ Substituents (Paper III) ........................... 56 4.5 P3P4 Urea Elongations (Paper III) .................................................. 61 4.6 Evaluation Towards the Genotype 3a of HCV NS3 Protease (Paper III) ........................................................................................ 64 5 Synthesis of Pyrazinone-Based HCV NS3 Protease Inhibitors (Papers II and III) ..................................................................................... 66 5.1 Formation of the 2(1H)-Pyrazinone Core ....................................... 66 5.2 Introduction of Urea Substituents ................................................... 68 5.3 Synthesis of P1P1’ Building Blocks ............................................... 70 5.4 Amide Coupling of P3 Pyrazinones and P1P1’ Building Blocks ... 73 5.5 Final Decorations and Modifications .............................................. 74 6 Method Development (Papers IV and V) ................................................. 76 6.1 Palladium as a Catalyst in Organic Synthesis ................................. 76 6.2 C-N Urea Arylation ......................................................................... 76 6.3 Palladium Catalyzed Urea Couplings to 3,5-Dichloro-2(1H)- Pyrazinones (Paper IV) ................................................................... 77 6.4 Palladium Catalyzed Carbonylations .............................................. 84 6.5 Synthesis of Acyl Sulfinamide, a Versatile Functionality (Paper V) .......................................................................................
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