DOCSLIB.ORG

Wo 2012/048204 A2

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Wo 2012/048204 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date _ . _ ... _ 12 April 2012 (12.04.2012) WO 2012/048204 A2 (51) International Patent Classification: (74) Agents: TYLER-CROSS, Ruth, E. et al; Whitham, A61K 47/48 (2006.01) A61K 31/426 (2006.01) Curtis, Christofferson & Cook, P.c, 11491 Sunset Hills A61K 47/30 (2006.01) A61K 31/505 (2006.01) Road, Suite 340, Reston, VA 20190 (US). A61K 9/127 (2006.01) A61K 31/573 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/US201 1/05523 1 AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (22) International Filing Date: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 7 October 201 1 (07.10.201 1) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (25) Filing Language: English KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (26) Publication Langi English NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, (30) Priority Data: RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, 61/391,1 77 8 October 2010 (08.10.2010) US TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant (for all designated States except US): VIR¬ GINIA COMMONWEALTH UNIVERSITY [US/US]; (84) Designated States (unless otherwise indicated, for every 800 East Leigh Street, Suite 113, Richmond, VA kind of regional protection available): ARIPO (BW, GH, 23298-0568 (US). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, (72) Inventors; and RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, (75) Inventors/ Applicants (for US only): WALSH, Scott, W. DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, [US/US]; 8900 Whistling Swan Road, Chesterfield, VA LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, 23838-8937 (US). GERK, Phillip, M. [US/US]; 10939 SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, Emerald Rock Lane, Mechnicsville, VA 23116-5865 GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (US). WANG, Meng [CN/US]; 104 West Franklin Street, Room 905, Richmond, VA 23220-5010 (US). LANDS- Published: BERG, Andrew, K. [US/US]; 264 Eagle Drive, Unit — without international search report and to be republished 102, Eagle-vail, CO 81620-3777 (US). upon receipt of that report (Rule 48.2(g)) (54) Title: PRODRUGS UTILIZING A TRANSPORTER DIRECTED UPTAKE MECHANISM Therapeutic aaent (such as lopinavir) Covalent linkage (such as ester bond) Spacer chain (such as C2-0-C2) < Hvdrophilic group (such o as carboxylic acid, COOH) ∞ Figure 1 © (57) Abstract: Prodrugs comprising a lipophilic drug linked to a transport moiety that can be taken up by a fatty acid transporter are provided. The transport moiety comprises a lipid chain connected to a hydrophilic group (e.g. a carboxylic acid, a phosphate, o or a sphingosine-like moiety). Due to the presence of the transport moiety, the prodrugs are substrates for endogenous fatty acid transporter systems. The transport moiety thus serves as a carrier or targeting moiety to facilitate uptake of the entire prodrug com plex by endogenous fatty acid transporter systems, thereby moving the prodrug into cells and tissues where drug distribution and o effects are desired. Hydrolysis of the chemical linkage between the lipid-like moiety and the lipophilic drug releases the drug in an active form within the cells or tissues. PRODRUGS UTILIZING A TRANSPORTER DIRECTED UPTAKE MECHANISM DESCRIPTION BACKGROUND OF THE INVENTION Field of the Invention The invention relates to the delivery of prodrugs to a desired site of action via uptake by endogenous lipid transport mechanisms. The prodrugs comprise a drug (e.g. a large, lipophilic drug) linked, via a hydrolyzable chemical bond, to a transport moiety that causes the prodrug to be taken up by a fatty acid transporter. Background of the Invention The development of methods for the targeted delivery of drugs to a site of action in an active form is a desideratum in the medical field that warrants the expenditure of hundreds of millions of dollars each year. Technologies have been developed whereby moieties that enhance solubility, permeability and stability are attached to drugs, e.g. via ester linkages. Recently, patents have issued for transporter directed prodrug approaches which utilize, for example, peptide transporters such as hPEPTl/2, monocarboxylate transporters such as MCTl-4, and multivitamin transporters such as SMVT to enhance uptake of drugs from the gastrointestinal tract. See, for example, US patent 7,671,082 to Moher, and US patent applications 2003/0158089 to Gallop et al. and 2005/0025839 to Polli, the compete contents of each of which are hereby incorporated by reference. In these cases, a moiety that is readily taken up by a transporter protein and translocated across the cell membrane is attached to a drug of interest, and the entire drug-moiety complex is taken up by the transporter and delivered into the cell. However, these transporters have only a limited capacity to accept large, lipophilic compounds, such as certain promising compounds used in the treatment of cancer and HIV. United States patent application 20090123388 to Ganapathy et al. (Prodrugs of Short-Chain Fatty Acids and Treatment Methods) is based on the discovery that the ATB + amino acid transport system can be used to transport prodrugs comprising a neutral or cationic amino acid that has been modified to comprise a short-chain fatty acid moiety, such as butyrate or pyruvate, into affected cells where the short-chain fatty acids exert their beneficial effect. These prodrugs are useful for treatment of colon cancer, inflammatory bowel disease, ulcerative colitis, Crohn's disease, lung cancer, cervical cancer, and cancers resulting from metastases from primary colon cancer sites. However, this prodrug system is also not designed to deliver large, lipophilic drugs. Sohma et al, (J. Med. Chem. 2003, 46, 4124-4135) describe the development of water soluble prodrugs of the V- protean inhibitor K -727 (amprenavir). The prodrugs comprise both amprenavir and a hydrophilic solubilizing moiety linked to drug via a self- cleaveable spacer. However, this study fails to suggest or take into account potentially advantageous transport mechanisms within cells or tissues. Matsumoto et al., [Bioorganic & Medicinal Chemistry 9 (2001) 417-430] describe prodrug forms of HIV protease inhibitors. However, this research group reached the conclusion that the presence of free carboxylic acids in the prodrug deterred penetration of the prodrug across the cell membrane. This may have been because they failed to recognize the importance of using a suitably ionizable group in the prodrug, or to take into account potentially advantageous transport mechanisms within cells or tissues. US patent 5,914,332 to Sham, et al. describes lopinavir derivatives, but does not show or suggest modifications of lopinavir which facilitate uptake into cells or tissues, or which take into account the time of bioavailabiltiy of the drug. There is an ongoing need to develop additional drug delivery strategies, particularly for large, lipophilic compounds. SUMMARY OF THE INVENTION The invention expands the realm of transporter-directed prodrug approaches to drug delivery, particularly the delivery of large, lipophilic molecules, by utilizing the previously unexploited fatty acid uptake and transporting system. According to the invention, a drug or molecule of interest is converted into a substrate for uptake by a fatty acid transporter by the attachment of a transport moiety, converting the drug to a prodrug that readily binds to and is taken up by the transporter. The transport moiety, which comprises a lipophilic spacer chain and a hydrophilic group, thus acts as a carrier or targeting moiety for uptake of the entire prodrug structure via the fatty acid transport system. Attachment of the drug to the transport moiety is generally via a chemical bond that is susceptible to hydrolysis. Therefore, once inside a cell or tissue of interest, the transport moiety is cleaved (hydrolyzed) from the prodrug structure, releasing the drug in an active form. In some embodiments, the prodrugs are advantageously ionizable at physiological H, at levels which provide suitable or reasonable prodrug halflives, having components with a pKa at or below 4.2. Because this prodrug system utilizes fatty acid transporters for uptake, the system is particularly useful for the delivery of drugs, especially large, lipophilic drugs, to areas of the body which were previously difficult to target, for example, the fetal placental unit, the central nervous system, gut-associated lymphatic tissue, the brain, and tumors. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. Schematic representation of uptake of a prodrug of the invention via a fatty acid transport system into target cells or tissues. Figure 2A-I. Structures of exemplary HIV Protease Inhibitors (HIVPI's). A, amprenavir; B, darunavir; C, atazanavir; D, indinavir; E, lopinavir; F, nelfinavir; G, ritonavir; H, saquiinavir; I, tipranavir; Arrows show hydroxyl groups susceptible to conjugation to a lipid-like structure. Figure 3A-Y. Exemplary prodrugs. A, succinyl-lopinavir; , diglycolic (diacetic)-lopinovir; C, thiodiglycolic (thiodiacetic)-lopinavir; D, fumaryl-lopinavir; E, muconyl-lopinavir;
Load more

Recommended publications
  • WO 2018/005909 Al 04 January 2018 (04.01.2018) W !P O PCT
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/005909 Al 04 January 2018 (04.01.2018) W !P O PCT (51) International Patent Classification: A61P 31/12 (2006 .01) A61K 31/505 (2006 .0 1) A61K 31/4985 (2006.01) (21) International Application Number: PCT/US20 17/040 175 (22) International Filing Date: 30 June 2017 (30.06.2017) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/357,458 0 1 July 2016 (01 .07.2016) US (71) Applicant: VIIV HEALTHCARE COMPANY [US/US]; 25 1 Little Falls Drive, Wilmington, DE 19808 (US). (72) Inventor: SPREEN, William, R.; 5 Moore Drive, Re search Triangle Park, NC 27709-3398 (US). (74) Agent: HAN, William, T. et al; Glaxosmithkline, Glob al Patents, UW2220, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA 19406-0939 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
    [Show full text]
  • Download Article PDF/Slides
    Kan Lu, PharmD New Antiretrovirals for Based on a presentation at prn by Roy M. Gulick, md, mph the Treatment of HIV: Kan Lu, PharmD | Drug Development Fellow University of North Carolina School of Pharmacy Chapel Hill, North Carolina The View in 2006 Roy M. Gulick, md, mph Reprinted from The prn Notebook® | october 2006 | Dr. James F. Braun, Editor-in-Chief Director, Cornell Clinical Trials Unit | Associate Professor of Medicine, Meri D. Pozo, PhD, Managing Editor. Published in New York City by the Physicians’ Research Network, Inc.® Weill Medical College of Cornell University | New York, New York John Graham Brown, Executive Director. For further information and other articles available online, visit http://www.prn.org | All rights reserved. ©october 2006 substantial progress continues to be made in the arena of cokinetics and a long extracellular half-life of approximately 10 hours antiretroviral drug development. prn is again proud to present its annual (Zhu, 2003). During apricitabine’s development, a serious drug interac- review of the experimental agents to watch for in the coming months and tion with lamivudine (Epivir) was noted. Although the plasma years. This year’s review is based on a lecture by Dr. Roy M. Gulick, a long- concentrations of apricitabine were unaffected by coadministration of time friend of prn, and no stranger to the antiretroviral development lamivudine, the intracellular concentrations of apricitabine were reduced pipeline. by approximately sixfold. Additionally, the 50% inhibitory concentration To date, twenty-two antiretrovirals have been approved by the Food (ic50) of apricitabine against hiv with the M184V mutation was increased and Drug Administration (fda) for the treatment of hiv infection.
    [Show full text]
  • Ep 2531027 B1
    (19) TZZ ¥_Z _T (11) EP 2 531 027 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/4985 (2006.01) A61K 31/52 (2006.01) 06.05.2015 Bulletin 2015/19 A61K 31/536 (2006.01) A61K 31/513 (2006.01) A61K 38/55 (2006.01) A61P 31/18 (2006.01) (21) Application number: 11737484.3 (86) International application number: (22) Date of filing: 24.01.2011 PCT/US2011/022219 (87) International publication number: WO 2011/094150 (04.08.2011 Gazette 2011/31) (54) Therapeutic combination comprising dolutegravir, abacavir and lamivudine Therapeutische Zusammensetzung enthaltend Dolutegravir, Abacavir und Lamivudine Combinaison thérapeutique comprenant du dolutégravir, de l’abacavir et de la lamivudine (84) Designated Contracting States: (74) Representative: Gladwin, Amanda Rachel AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GlaxoSmithKline GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Global Patents (CN925.1) PL PT RO RS SE SI SK SM TR 980 Great West Road Designated Extension States: Brentford, Middlesex TW8 9GS (GB) BA ME (56) References cited: (30) Priority: 27.01.2010 US 298589 P WO-A1-2010/011812 WO-A2-2009/148600 US-A1- 2006 084 627 US-A1- 2006 084 627 (43) Date of publication of application: US-A1- 2008 076 738 US-A1- 2009 318 421 12.12.2012 Bulletin 2012/50 US-A1- 2009 318 421 US-B1- 6 544 961 (73) Proprietor: VIIV Healthcare Company • SONG1 et al: "The Effect of Ritonavir-Boosted Research Triangle Park, NC 27709 (US) ProteaseInhibitors on the HIV Integrase Inhibitor, S/GSK1349572,in Healthy Subjects", INTERNET , (72) Inventor: UNDERWOOD, Mark, Richard 15 September 2009 (2009-09-15), XP002697436, Research Triangle Park Retrieved from the Internet: URL:http: North Carolina 27709 (US) //www.natap.org/2009/ICCAC/ICCAC_ 52.htm [retrieved on 2013-05-21] Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations.
    [Show full text]
  • PHARMACEUTICAL APPENDIX to the TARIFF SCHEDULE 2 Table 1
    Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names INN which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service CAS registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known.
    [Show full text]
  • GSK and Vertex Pharmaceuticals Announce Presentation of Data Supporting Development of Investigational HIV Protease Inhibitor Brecanavir
    December 16, 2005 GSK and Vertex Pharmaceuticals Announce Presentation of Data Supporting Development of Investigational HIV Protease Inhibitor Brecanavir - Positive Data Presented at 45th Annual ICAAC - Cambridge, MA, December 16, 2005 - GlaxoSmithKline (GSK) and Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) presented positive results today from a study evaluating the safety, tolerability and antiviral activity of the investigational HIV-1 protease inhibitor (PI), brecanavir* (formerly known as GW640385 or VX-385)1. These data were presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) held in Washington DC. Interim findings following 24 weeks of dosing demonstrated potent antiviral activity for brecanavir in both PI-sensitive and PI-resistant HIV-infected adults. "These results support the ongoing development program for brecanavir, which is anticipated to enter Phase III development in 2006," said Lynn Marks, MD, Senior Vice President of the Infectious Disease Medicines Development Centre at GSK. "If approved, brecanavir may be useful in treating patients infected with strains of HIV that have become resistant to multiple protease inhibitors, and its clinical advancement underscores GSK's commitment to developing new anti-HIV drugs." Clinical Data on Brecanavir Brecanavir is an HIV protease inhibitor in Phase IIb clinical development. Brecanavir has received fast track designation from the U.S. Food and Drug Administration and is being developed by GSK as part of a collaboration with Vertex Pharmaceuticals. Data presented were from a planned, 24-week analysis of an open-label study (HPR10006) of 48 weeks' duration evaluating the safety, tolerability, antiviral activity and pharmacokinetics of ritonavir-boosted brecanavir. Thirty-one HIV-1 infected adults received 300mg of brecanavir twice-daily boosted with 100mg of ritonavir in combination with two nucleoside reverse transcriptase inhibitors based on patient medical history and viral genotype.
    [Show full text]
  • Screening of Clinically Approved and Investigation Drugs As Potential
    Screening of Clinically Approved and Investigation Drugs as Potential Inhibitors of COVID-19 Main Protease: A Virtual Drug Repurposing Study Serdar Durdagi1,*, Busecan Aksoydan1,2, Berna Dogan1, Kader Sahin1, Aida Shahraki1,3 1Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey 2Neuroscience Program, Graduate School of Health Sciences, Bahçeşehir University, Istanbul, Turkey 3Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey Abstract There is an urgent need for a new drug against COVID-19. Since designing a new drug and testing its pharmacokinetics and pharmacodynamics properties may take years, here we used a physics-driven high throughput virtual screening drug re-purposing approach to identify new compounds against COVID-19. As the molecules considered in repurposing studies passed through several stages and have well-defined profiles, they would not require prolonged pre- clinical studies and hence, they would be excellent candidates in the cases of disease emergencies or outbreaks. While the spike protein is the key for the virus to enter the cell though the interaction with ACE2, enzymes such as main protease are crucial for the life cycle of the virus. This protein is one of the most attractive targets for the development of new drugs against COVID-19 due to its pivotal role in the replication and transcription of the virus. We used 7922 FDA approved small molecule drugs as well as compounds in clinical investigation from NIH Chemical Genomics Center (NCGC) Pharmaceutical Collection (NPC) database in our drug repurposing study. Both apo and holo forms of target protein COVID-19 main proteases were used in virtual screening.
    [Show full text]
  • Section 2.6.4 Pharmacokinetics Written Summary EMTRICITABINE
    SECTION 2.6 NONCLINICAL SUMMARY Section 2.6.4 Pharmacokinetics Written Summary EMTRICITABINE/ RILPIVIRINE/ TENOFOVIR DISOPROXIL FUMARATE FIXED-DOSE COMBINATION 17 August 2010 CONFIDENTIAL AND PROPRIETARY INFORMATION Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Section 2.6.4 Pharmacokinetics Written Summary Final TABLE OF CONTENTS SECTION 2.6 NONCLINICAL SUMMARY........................................................................................................1 TABLE OF CONTENTS .......................................................................................................................................2 GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ..............................................................5 2.6. NONCLINICAL SUMMARY.......................................................................................................................8 2.6.4. PHARMACOKINETICS WRITTEN SUMMARY .........................................................................8 2.6.4.1. Brief Summary................................................................................................................8 2.6.4.2. Methods of Analysis .....................................................................................................14 2.6.4.2.1. Emtricitabine............................................................................................14 2.6.4.2.2. Rilpivirine ................................................................................................14 2.6.4.2.3. Tenofovir Disoproxil Fumarate
    [Show full text]
  • WO 2017/191545 Al 09 November 2017 (09.11.2017) W !P O PCT
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/191545 Al 09 November 2017 (09.11.2017) W !P O PCT (51) International Patent Classification: (84) Designated States (unless otherwise indicated, for every C07D 495/04 (2006.01) kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (21) International Application Number: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, PCT/IB20 17/052523 TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (22) International Filing Date: EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, 0 1 May 2017 (01 .05.2017) MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (25) Filing Language: English KM, ML, MR, NE, SN, TD, TG). (26) Publication Langi English Declarations under Rule 4.17: (30) Priority Data: — as to applicant's entitlement to apply for and be granted a 62/332,13 1 05 May 2016 (05.05.2016) US patent (Rule 4.1 7(H)) 62/359,904 08 July 2016 (08.07.2016) US — as to the applicant's entitlement to claim the priority of the 62/454,143 03 February 2017 (03.02.2017) US earlier application (Rule 4.17(Hi)) 62/482,964 07 April 2017 (07.04.20 17) US — of inventorship (Rule 4.1 7(iv)) (71) Applicant: GLAXOSMITHKLINE INTELLECTUAL Published: PROPERTY (NO.2) LIMITED [GB/GB] ; 980 Great West — with international search report (Art.
    [Show full text]
  • Current and Novel Inhibitors of HIV Protease
    Viruses 2009, 1, 1209-1239; doi:10.3390/v1031209 OPEN ACCESS viruses ISSN 1999-4915 www.mdpi.com/journal/viruses Review Current and Novel Inhibitors of HIV Protease Jana Pokorná 1,5, Ladislav Machala 2,3, Pavlína Řezáčová 1,4 and Jan Konvalinka 1,4,5,* 1 Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center, Flemingovo n. 2, 166 10, Prague 6, Czech Republic; E-Mails: [email protected] (J.P.); [email protected] (P.R.) 2 AIDS Center, Department of Infectious Diseases, University Hospital Bulovka, Budínova 2, 120 00, Prague 8, Czech Republic; E-Mail: [email protected] 3 Department of Infectious Diseases, Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic 4 Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10, Prague 6, Czech Republic 5 Department of Biochemistry, Faculty of Science, Charles University in Prague, Hlavova 8, 128 43, Prague 2, Czech Republic * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +420-220-183-218; Fax: +420-220-183-378. Received: 8 October 2009; in revised form: 7 December 2009 / Accepted: 7 December 2009 / Published: 11 December 2009 Abstract: The design, development and clinical success of HIV protease inhibitors represent one of the most remarkable achievements of molecular medicine. This review describes all nine currently available FDA-approved protease inhibitors, discusses their pharmacokinetic properties, off-target activities, side-effects, and resistance profiles. The compounds in the various stages of clinical development are also introduced, as well as alternative approaches, aiming at other functional domains of HIV PR.
    [Show full text]
  • N° 18583 C07d 239/94 (2018.01) C07d 401/12 (2018.01)
    19 ORGANISATION AFRICAINE DE LA PROPRIETE INTELLECTUELLE 51 8 Inter. CI. A61K 31/517 (2018.01) 11 A61P 31/18 (2018.01) N° 18583 C07D 239/94 (2018.01) C07D 401/12 (2018.01) FASCICULE DE BREVET D'INVENTION 21 Numéro de dépôt : 1201700237 73 Titulaire(s): PCT/US2015/000460 GILEAD SCIENCES, INC., 333 Lakeside Drive, 22 Date de dépôt : 23/12/2015 FOSTER CITY, CA 94404 (US) INSTITUTE OF ORGANIC CHEMISTRY AND BIOCHEMISTRY OF THE AS CR, 30 Priorité(s): V.V.I., Flemingovo Nam. 2, 166 10 PRAHA 6 (CZ) US n° 62/096,748 du 24/12/2014 Inventeur(s): 72 HU Yunfeng Eric (US) MACKMAN Richard L. (US) LANSDON Eric (c/o Gilead Sciences, Inc. (US) JANSA Petr (US) SIMON Petr (CZ) BASZCZYNSKI Ondrej (CZ) DEJMEK Milan (CZ) 24 Délivré le : 11/12/2018 74 Mandataire: GAD CONSULTANTS SCP, 45 Publié le : 28.12.2018 B.P. 13448, YAOUNDE (CM). 54 Titre: Quinazoline derivatives used to treat HIV. 57 Abrégé : and tautomers and pharmaceutical salts thereof, compositions and formulations containing such Described herein are compounds of Formula compounds, and methods of using and making such compounds. O.A.P.I. – B.P. 887, YAOUNDE (Cameroun) – Tel. (237) 222 20 57 00 – Site web: http:/www.oapi.int – Email: [email protected] 18583 QUINAZOLINE DERIVATIVES USED TO TREAT IIIV CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority benefit to U.S. Application Serial No. 62/096,748, filed December 24, 2014, the disclosure of which is herein incorporated by reference in its entirety. BACKGROUND [0002] While progress has been made in treating 111V and AIDS, HIV infection remains a global health concern.
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • Antiviral Drugs in the Treatment of Aids: What Is in the Pipeline ?
    October 15, 2007 EU RO PE AN JOUR NAL OF MED I CAL RE SEARCH 483 Eur J Med Res (2007) 12: 483-495 © I. Holzapfel Publishers 2007 ANTIVIRAL DRUGS IN THE TREATMENT OF AIDS: WHAT IS IN THE PIPELINE ? Hans-Jürgen Stellbrink Infektionsmedizinisches Centrum Hamburg ICH, Hamburg, Germany Abstract even targeting immune responses have to be devel- Drug development in the field of HIV treatment is oped. Continued drug development serves the ulti- rapid. New nucleoside analogues (NRTI), non-nucleo- mate goal of normalization of life expectancy. side analogue reverse transcriptase inhibitors (NNR- TI), and protease inhibitors (PI) are currently being in- METHODS vestigated in human trials. Furthermore, inhibitors of HIV attachment, fusion and integrase with novel Drug development in the field of HIV infection is modes of action are being developed, which offer new highly competitive, and a company’s decision to pur- perspectives for the goal of a normalization of life-ex- sue or discontinue the development of a drug is dri- pectancy in HIV-infected individuals. The most ad- ven by economic rather than scientific considerations. vanced compounds likely to become licensed soon in- Of all candidate compounds, only a few reach the lev- clude the NNRTIs rilpivirine and etravirine, the inte- el of trials in humans, and some exhibit lack of effica- grase inhibitors raltegravir and elvitegravir, and mar- cy or toxicity problems at this stage. Some compounds aviroc and vicriviroc, novel inhibitors of the CCR5 also have no obvious advantage over currently avail- chemokine receptor, which functions as the major able ones, so that their development is discontinued.
    [Show full text]