DOCSLIB.ORG

(10) Patent No.: US 9309235 B2

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(10) Patent No.: US 9309235 B2 US0093 09235B2 (12) United States Patent (10) Patent No.: US 9,309,235 B2 m et al. (45) Date of Patent: Apr. 12, 2016 (54) SGC STIMULATORS 9,061,030 B2 * 6/2015 Kim ..................... CO7D 401/04 9,139,564 B2 * 9/2015 Kim ..................... CO7D 413/14 (71) Applicant: IRONWOOD PHARMACEUTICALS, 2010/0.144864 A1* 6, 2010 Currie .................... A61K 31/04 514,470 INC., Cambridge, MA (US) 2013/O123354 A1* 5, 2013 Currie .................... A61K 31/04 514,470 (72) Inventors: G-Yoon Jamie Im, Cambridge, MA 2013,01784.75 A1* 7, 2013 Moore ................. CO7D 401/04 (US); Rajesh Iyengar, West Newton, 514,245 MA (US); Joel Moore, Lexington, MA 2014/0088071 A1 3/2014 Nakai .................. CO7D 401/04 ...i. s 514,2102 (US); Angelika Fretzen, Somerville, 2014/0323448 A1* 10/2014 Kim ................... A61K 31/4155 MA (US) 514,171 2015,0018353 A1 1/2015 Kim ..................... CO7D 413/14 (73) Assignee: IRONWOOD PHARMACEUTICALS, 514,236.5 INC., Cambridge, MA (US) 2015,0250795 A1* 9, 2015 Kim ..................... CO7D 401/04 424,613 (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 FOREIGN PATENT DOCUMENTS U.S.C. 154(b) by 0 days. WO WO 2011 126903 A2 * 10, 2011 ......... A61K 31,4427 WO 2012OO3405 A1 1, 2012 (21) Appl. No.: 14/428,844 WO 2012O64559 A1 5, 2012 WO 2012O75678 A1 6, 2012 (22) PCT Filed: Sep. 18, 2013 (86). PCT No.: PCT/US2O13/06O295 OTHER PUBLICATIONS S371 (c)(1), International Search Report for PCT/US2013/060295 dated Oct. 25, (2) Date: Mar. 17, 2015 2013. (87) PCT Pub. No.: WO2014/047111 * cited by examiner PCT Pub. Date: Mar. 27, 2014 (65) Prior Publication Data Pririmary Examiner — Al CXaCder RPagano (74) Attorney, Agent, or Firm — Heslin, Rothenberg, Farley US 2015/O274712 A1 Oct. 1, 2015 & Mesiti, P.C. Related U.S. Application Data (60) Provisional application No. 61/702,303, filed on Sep. (57) ABSTRACT 18, 2012. s Compounds of Formula I are described. They are useful as (51) Int. Cl. stimulators of sGC, particularly NO-independent, heme-de A6 IK3I/506 (2006.01) pendent stimulators. These compounds may be useful for CO7D 413/4 (2006.01) treating, preventing or managing various disorders that are A6 IK3I/53 (2006.01) herein disclosed. CO7D 407/14 (2006.01) CO7D 409/14 (2006.01) (52) U.S. Cl. Formula I CPC ............ C07D 413/14 (2013.01); A61 K3I/506 (2013.01); A61 K3I/513 (2013.01); C07D C 407/14 (2013.01); C07D 409/14 (2013.01) R N (JP), (58) Field of Classification Search N CPC. C07D407/14: CO7D 409/14: A61K 31/506; A. / A61K 3.1 F513 R See application file for complete search history. 7 N X (56) References Cited D y S. X D U.S. PATENT DOCUMENTS (J')o 7,300,950 B2 * 1 1/2007 Schindler ............. CO7D405/04 514,405 8,748.442 B2 * 6/2014 Kim ................... A61K 31/4155 514,269 25 Claims, No Drawings US 9,309,235 B2 1. 2 SGC STIMULATORS Treatment with NO-independent sGC stimulators also pro moted Smooth muscle relaxation in the corpus cavernosum of CROSS REFERENCE TO RELATED healthy rabbits, rats and humans, causing penile erection, APPLICATIONS indicating that SGC stimulators are useful for treating erectile dysfunction. This patent application is a 371 filing of PCT/US2013/ NO-independent, heme-dependent, sGC stimulators, such 060295, filed 18 Sep. 2013, which claims the benefit of U.S. as those disclosed herein, have several important differenti Provisional Application No. 61/702.303 filed 18 Sep. 2012, ating characteristics, including crucial dependency on the the disclosures of which are herein incorporated by reference presence of the reduced prosthetic heme moiety for their in their entirety. 10 activity, strong Synergistic enzyme activation when combined with NO and stimulation of the synthesis of c(GMP by direct FIELD OF THE INVENTION stimulation of sGC, independent of NO. The benzylindazole compound YC-1 was the first sGC stimulator to be identified. The present disclosure relates to stimulators of soluble 15 Additional sGC stimulators with improved potency and guanylate cyclase (sGC), pharmaceutical formulations com specificity for sGC have since been developed. These com prising thereof and their uses, alone or in combination with pounds have been shown to produce anti-aggregatory, anti one or more additional agents, for treating and/or preventing proliferative and vasodilatory effects. various diseases, wherein an increase in the concentration of Since compounds that stimulate sGC in an NO-indepen nitric oxide (NO) or an increase in the concentration of cyclic dent manner offer considerable advantages over other current Guanosine Monophosphate (cGMP) might be desirable. alternative therapies, there is a need to develop novel stimu lators of sGC. They are potentially useful in the prevention, BACKGROUND OF THE INVENTION management and treatment of disorders such as pulmonary hypertension, arterial hypertension, heart failure, atheroscle Soluble guanylate cyclase (sGC) is the primary receptor for 25 rosis, inflammation, thrombosis, renal fibrosis and failure, nitric oxide (NO) in vivo. sGC can be activated via both liver cirrhosis, lung fibrosis, erectile dysfunction, female NO-dependent and NO-independent mechanisms. In sexual arousal disorder and vaginal atrophy and other cardio response to this activation, sGC converts GTP into the sec vascular disorders; they are also potentially useful for the ondary messenger cyclic GMP (cGMP). The increased level prevention, management and treatment of lipid related disor ofcCMP in turn, modulates the activity of downstream effec 30 ders. tors including protein kinases, phosphodiesterases (PDES) and ion channels. SUMMARY OF THE INVENTION In the body, NO is synthesized from arginine and oxygen by various nitric oxide synthase (NOS) enzymes and by The present invention is directed to compounds according sequential reduction of inorganic nitrate. Three distinct iso 35 to Formula I, or pharmaceutically acceptable salts thereof, forms of NOS have been identified: inducible NOS (iNOS or NOS II) found in activated macrophage cells; constitutive neuronal NOS (nNOS or NOS I), involved in neurotransmis Formula I sion and long term potentiation; and constitutive endothelial NOS (eNOS or NOS III) which regulates smooth muscle 40 RC relaxation and blood pressure. N Experimental and clinical evidence indicates that reduced Y (JP), bioavailability and/or responsiveness to endogenously pro A duced NO contributes to the development of cardiovascular, R4 endothelial, renal and hepatic disease, as well as erectile 45 dysfunction and other sexual disorders (e.g. female sexual % N disorder or vaginal atrophy). In particular, the NO signaling pathway is altered in cardiovascular diseases, including, for \:S. instance, systemic and pulmonary hypertension, heart failure, X.)o angina, stroke, thrombosis and other thromboembolic dis 50 eases, peripheral arterial disease, fibrosis of the liver, lung or wherein: kidney and atherosclerosis. ring B is a 5-membered heteroaryl ring selected from furan or sGC stimulators are also useful in the treatment of lipid thiophene; related disorders such as e.g., dyslipidemia, hypercholester n is an integer selected from 0 to 3: olemia, hypertriglyceridemia, sitosterolemia, fatty liver dis 55 each J is independently selected from halogen, —CN, a C ease, and hepatitis. aliphatic, —OR or a Css cycloaliphatic group; wherein Pulmonary hypertension (PH) is a disease characterized by each said Caliphatic and each said C.s cycloaliphatic Sustained elevation of blood pressure in the pulmonary vas group is optionally and independently Substituted with up culature (pulmonary artery, pulmonary vein and pulmonary to 3 instances of R: capillaries), which results in right heart hypertrophy, eventu 60 each R is independently selected from hydrogen, a C ally leading to right heart failure and death. In PH, the bioac aliphatic or a C-s cycloaliphatic ring; wherein each said tivity of NO and other vasodilators such as prostacyclin is Caliphatic and each said C.s cycloaliphatic ring is reduced, whereas the production of endogenous vasocon optionally and independently substituted with up to 3 strictors such as endothelin is increased, resulting in exces instances of R". sive pulmonary vasoconstriction. SGC stimulators have been 65 each R is independently selected from halogen, —CN, C used to treat PH because they promote smooth muscle relax alkyl, Ca haloalkyl, —O(C. alkyl) or —O(C- ation, which leads to vasodilation. haloalkyl); US 9,309,235 B2 3 4 each R" is independently selected from halogen, —CN, C 5-membered heteroaryl ring; wherein each said 4 to alkyl, Ca haloalkyl, -O(C. alkyl) or —O(C- 8-membered heterocyclic ring and each said 5-membered haloalkyl); heteroaryl ring optionally contains up to 2 additional het X is selected from N, C-JP or C H: eroatoms independently selected from N, O or S, and is an integer selected from 0 to 3: wherein each said 4 to 8-membered heterocyclic ring and each JP is independently selected from halogen, NO, each said 5-membered heteroaryl ring is optionally and OR', SR, C(O)R’, C(O)OR, C(O)N(R), independently substituted by up to 3 instances of R: CN, N(RP), N(R)C(O)RP, N(R)C(O)ORP, when Jis-N(R)C(O)ORP, the RP group together with the - SORP, -SON(RP), -N (R)SORP, a C- ali oxygen atom attached to the RP group, with the carbon phatic. —(Caliphatic)-R', a Css cycloaliphatic ring, a 6 10 atom of the -C(O)— portion of the N(R')C(O)ORP to 10-membered aryl ring, a 4 to 8-membered heterocyclic group, with the nitrogenatom attached to the R group, and ring or a 5 to 10-membered heteroaryl ring; wherein each with the R group alternatively form a 4 to 8-membered said 4 to 8-membered heterocylic ring and each said 5 to heterocyclic ring or a 5-membered heteroaryl ring; 10-membered heteroaryl ring contains between 1 and 3 wherein each said 4 to 8-membered heterocyclic ring and heteroatoms independently selected from O, N or S; and 15 each said 5-membered heteroaryl ring optionally contains wherein each said C.
Load more

Recommended publications
  • Endothelin System and Therapeutic Application of Endothelin Receptor
    xperim ACCESS Freely available online & E en OPEN l ta a l ic P in h l a C r m f o a c l a o n l o r g u y o J Journal of ISSN: 2161-1459 Clinical & Experimental Pharmacology Research Article Endothelin System and Therapeutic Application of Endothelin Receptor Antagonists Abebe Basazn Mekuria, Zemene Demelash Kifle*, Mohammedbrhan Abdelwuhab Department of Pharmacology, School of Pharmacy, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia ABSTRACT Endothelin is a 21 amino acid molecule endogenous potent vasoconstrictor peptide. Endothelin is synthesized in vascular endothelial and smooth muscle cells, as well as in neural, renal, pulmonic, and inflammatory cells. It acts through a seven transmembrane endothelin receptor A (ETA) and endothelin receptor B (ETB) receptors belongs to G protein-coupled rhodopsin-type receptor superfamily. This peptide involved in pathogenesis of cardiovascular disorder like (heart failure, arterial hypertension, myocardial infraction and atherosclerosis), renal failure, pulmonary arterial hypertension and it also involved in pathogenesis of cancer. Potentially endothelin receptor antagonist helps the treatment of the above disorder. Currently, there are a lot of trails both per-clinical and clinical on endothelin antagonist for various cardiovascular, pulmonary and cancer disorder. Some are approved by FAD for the treatment. These agents are including both selective and non-selective endothelin receptor antagonist (ETA/B). Currently, Bosentan, Ambrisentan, and Macitentan approved
    [Show full text]
  • THELIN, INN-Sitaxentan Sodium
    European Medicines Agency Evaluation of Medicines for Human Use London, 17 December 2009 Doc. Ref EMA/831836/2009 ASSESSMENT REPORT FOR Thelin International non-proprietary name/Common name: sitaxentan sodium EMEA/H/C/000679/II/0018 Variation Assessment Report as adopted by theauthorised CHMP with all information of a commercially confidential nature deleted longer no product Medicinal 7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 86 13 E-mail: [email protected] http://www.ema.europa.eu European Medicines Agency, 2009. Reproduction is authorised provided the source is acknowledged. I. SCIENTIFIC DISCUSSION 1.1. Introduction Thelin contains sitaxentan sodium, which is an endothelin receptor antagonist, with higher selectivity for the ETA receptor than the ETB receptor subtype. Endothelin-1 (ET-1) is a potent vascular paracrine and autocrine peptide in the lung, and can also promote fibrosis, cell proliferation, cardiac hypertrophy and remodeling, and is pro-inflammatory. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension (PAH), as well as other cardiovascular disorders and connective tissue diseases, including scleroderma, acute and chronic heart failure, myocardial ischaemia, systemic hypertension, and atherosclerosis, suggesting a pathogenic role of ET- 1 in these diseases. In PAH and heart failure, in the absence of endothelin receptor antagonism, elevated ET-1 concentrations are strongly correlated with the severity and prognosis of these diseases. Additionally, PAH is also characterised by reduced nitric oxide activity. ET-1 actions are mediated through endothelin A receptors (ETA), present on smooth muscle cells, and endothelin B receptors (ETB), present on endothelial cells.
    [Show full text]
  • Corrigendum Doi:10.1093/Eurheartj/Ehr046
    Corrigendum doi:10.1093/eurheartj/ehr046 ............................................................................................................................................................................. Corrigendum to: ‘Guidelines for the diagnosis and treatment of pulmonary hypertension’ [European Heart Journal (2009) 30, 2493–2537]. The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Authors/Task Force Members: Nazzareno Galie` (Chairperson) (Italy); Marius M. Hoeper (Germany); Marc Humbert (France); Adam Torbicki (Poland); Jean-Luc Vachiery (France); Joan Albert Barbera (Spain); Maurice Beghetti (Switzerland); Paul Corris (UK); Sean Gaine (Ireland); J. Simon Gibbs (UK); Miguel Angel Gomez-Sanchez (Spain); Guillaume Jondeau (France); Walter Klepetko (Austria) Christian Opitz (Germany); Andrew Peacock (UK); Lewis Rubin (USA); Michael Zellweger (Switzerland); Gerald Simonneau (France). Withdrawal of sitaxentan in the treatment of pulmonary arterial hypertension The 2009 ESC Practice Clinical Guidelines for the diagnosis and treatment of pulmonary hypertension included the endothelin receptor antag- onist sitaxentan in an algorithm of evidence-based treatment for pulmonary arterial hypertension. Sitaxentan was recommended with a Class I/Level A grade of evidence in WHO functional class III patients and Class IIa/Level C grade of evidence
    [Show full text]
  • The Mechanisms of Action of Ppars
    12 Dec 2001 8:6 AR AR149-24.tex AR149-24.SGM LaTeX2e(2001/05/10) P1: GSR Annu. Rev. Med. 2002. 53:409–35 Copyright c 2002 by Annual Reviews. All rights reserved THE MECHANISMS OF ACTION OF PPARS Joel Berger and David E. Moller Department of Molecular Endocrinology, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065; e-mail: joel [email protected]; david [email protected] Key Words PPAR, nuclear receptors, diabetes, dyslipidemia ■ Abstract The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPAR ,PPAR, and PPAR, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with co- factors such that the rate of transcription initiation is increased. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Fatty acids and eicosanoids have been identified as natural ligands for the PPARs. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, have proven effective in the treatment of dyslipidemia and diabetes. Use of such ligands has allowed researchers to unveil many potential roles for the PPARs in pathological states including atherosclerosis, inflammation, cancer, infertility, and demyelination. Here, we present the current state of knowledge regarding the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases. INTRODUCTION The peroxisome proliferator-activated receptors (PPARs) form a subfamily of the nuclear receptor superfamily.
    [Show full text]
  • Diabetes-Related Biomarkers and Methods of Use Thereof
    (19) TZZ _ _T (11) EP 2 541 254 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: G01N 21/76 (2006.01) G01N 21/64 (2006.01) 12.11.2014 Bulletin 2014/46 G01N 33/66 (2006.01) G01N 33/74 (2006.01) G01N 33/68 (2006.01) (21) Application number: 12175286.9 (22) Date of filing: 18.04.2008 (54) Diabetes-related biomarkers and methods of use thereof Diabetesassoziierte Biomarker und Verfahren zur deren Verwendung dafür Biomarqueurs associés aux diabètes et procédés d’utilisation correspondants (84) Designated Contracting States: • HANLEY ANTHONY J G ET AL: "Metabolic and AT BE BG CH CY CZ DE DK EE ES FI FR GB GR inflammation variable clusters and prediction of HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT type 2 diabetes: factor analysis using directly RO SE SI SK TR measured insulin sensitivity.", DIABETES JUL 2004, vol. 53, no. 7, July 2004 (2004-07), pages (30) Priority: 18.04.2007 US 788260 1773-1781, XP002486180, ISSN: 0012-1797 08.11.2007 US 2609 P • EDELMAN DAVID ET AL: "Utility of hemoglobin A1c in predicting diabetes risk", JOURNAL OF (43) Date of publication of application: GENERAL INTERNAL MEDICINE, vol. 19, no. 12, 02.01.2013 Bulletin 2013/01 December 2004 (2004-12), pages 1175-1180, XP002502995, ISSN: 0884-8734 (62) Document number(s) of the earlier application(s) in • INOUE ET AL: "The combination of fasting accordance with Art. 76 EPC: plasma glucose and glycosylated hemoglobin 08746276.8 / 2 147 315 predicts type 2 diabetes in Japanese workers", DIABETES RESEARCH AND CLINICAL (73) Proprietor: Health Diagnostic Laboratory, Inc.
    [Show full text]
  • Access to New Medicines in New Zealand Compared to Australia
    THE NEW ZEALAND MEDICAL JOURNAL Journal of the New Zealand Medical Association Access to new medicines in New Zealand compared to Australia Michael Wonder, Richard Milne Abstract Aim To compare access to new prescription-only medicines in New Zealand (NZ) with that in Australia. Method The range of new prescription medicines and the timing of their regulatory approval and reimbursement in NZ and Australia in the period 2000 to 2009 were compared. Results 136 new prescription medicines were first listed in the Australian Schedule of Pharmaceutical Benefits in the study period and 59 (43%) of these were listed in the NZ Pharmaceutical Schedule. Listing of these 59 medicines for reimbursement occurred later in NZ (mean difference=32.7 months; 95% CI 24.2 to 41.2 months; p<0.0001) due largely to a longer time from registration to listing (mean difference=23.7 months; 95% CI 14.9 to 32.4 months; p<0.0001). The remaining 77 medicines that are reimbursed in Australia but not in NZ cover a wide range of therapeutic areas, including some diseases for which there are no reimbursed medicines in NZ. Four new medicines were listed in NZ but not Australia. Conclusion In the last decade, public access to new medicines in NZ has been more limited and delayed compared to Australia. Access to new medicines is an ongoing public health issue in most developed countries. Many new medicines are costly and unaffordable for many patients; therefore public access is very limited. Governments are under continual pressure to provide timely access to new medicines, many of which are costly.
    [Show full text]
  • Englitazone Administration to Late Pregnant Rats Produces Delayed Body Growth and Insulin Resistance in Their Fetuses and Neonates
    Biochem. J. (2005) 389, 913–918 (Printed in Great Britain) 913 Englitazone administration to late pregnant rats produces delayed body growth and insulin resistance in their fetuses and neonates Julio SEVILLANO, Inmaculada C. LOPEZ-P´ EREZ,´ Emilio HERRERA, Mar´ıa DEL PILAR RAMOS and Carlos BOCOS1 Facultad de Farmacia, Universidad San Pablo-CEU, Montepr´ıncipe, Ctra. Boadilla del Monte Km 5.300, E-28668 Boadilla del Monte (Madrid), Spain The level of maternal circulating triacylglycerols during late preg- pregnant rats was corroborated, since they showed higher plasma nancy has been correlated with the mass of newborns. PPARγ NEFA [non-esterified (‘free’) fatty acid] levels, ketonaemia and (peroxisome-proliferator-activated receptor γ ) ligands, such as liver LPL (lipoprotein lipase) activity and lower plasma IGF-I TZDs (thiazolidinediones), have been shown to reduce triacyl- (type 1 insulin-like growth factor) levels, in comparison with glycerolaemia and have also been implicated in the inhibition those from control mothers. Moreover, at the molecular level, an of tissue growth and the promotion of cell differentiation. increase in Akt phosphorylation was found in the liver of neonates Therefore TZDs might control cell proliferation during late fetal from EZ-treated mothers, which confirms that the insulin pathway development and, by extension, body mass of pups. To investigate was negatively affected. Thus the response of fetuses and neonates the response to EZ (englitazone), a TZD, on perinatal develop- to maternal antidiabetic drug treatment is the opposite of what ment, 0 or 50 mg of englitazone/kg of body mass was given as an would be expected, and can be justified by the scarce amount of oral dose to pregnant rats daily from day 16 of gestation until either adipose tissue impeding a normal response to PPARγ ligands and day 20 for the study of their fetuses, or until day 21 of gestation by hyperinsulinaemia as being responsible for a major insulin- for the study of neonates.
    [Show full text]
  • Modifications to the Harmonized Tariff Schedule of the United States To
    U.S. International Trade Commission COMMISSIONERS Shara L. Aranoff, Chairman Daniel R. Pearson, Vice Chairman Deanna Tanner Okun Charlotte R. Lane Irving A. Williamson Dean A. Pinkert Address all communications to Secretary to the Commission United States International Trade Commission Washington, DC 20436 U.S. International Trade Commission Washington, DC 20436 www.usitc.gov Modifications to the Harmonized Tariff Schedule of the United States to Implement the Dominican Republic- Central America-United States Free Trade Agreement With Respect to Costa Rica Publication 4038 December 2008 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 18, 2008, set forth in the Appendix hereto, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement the Dominican Republic- Central America-United States Free Trade Agreement, as approved in the Dominican Republic-Central America- United States Free Trade Agreement Implementation Act, with respect to Costa Rica. (This page is intentionally blank) Annex I Effective with respect to goods that are entered, or withdrawn from warehouse for consumption, on or after January 1, 2009, the Harmonized Tariff Schedule of the United States (HTS) is modified as provided herein, with bracketed matter included to assist in the understanding of proclaimed modifications. The following supersedes matter now in the HTS. (1). General note 4 is modified as follows: (a). by deleting from subdivision (a) the following country from the enumeration of independent beneficiary developing countries: Costa Rica (b).
    [Show full text]
  • Possible Role of Rivoglitazone Thiazolidine Class of Drug As Dual
    Medical Hypotheses 131 (2019) 109305 Contents lists available at ScienceDirect Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy Possible role of rivoglitazone thiazolidine class of drug as dual-target therapeutic agent for bacterial infections: An in silico study T ⁎ Vidyasrilekha Yele , Niladri Saha, Afzal Azam Md Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Ootacamund, JSS Academy of Higher Education & Research, Mysuru 643001, India ARTICLE INFO ABSTRACT Keywords: Infections due to resistant bacteria are the life-threatening and leading cause of mortality worldwide. The Rivoglitazone current therapy for bacterial infections includes treatment with various drugs and antibiotics. The misuse and ParE over usage of these antibiotics leads to bacterial resistance. There are several mechanisms by which bacteria MurE exhibit resistance to some antibiotics. These include drug inactivation or modification, elimination of antibiotics Docking through efflux pumps, drug target alteration, and modification of metabolic pathway. However, it is difficult to MM-GBSA treat infections caused by resistant bacteria by conventional existing therapy. In the present study binding af- Molecular dynamic simulations fi Anti-bacterial agent nities of some glitazones against ParE and MurE bacterial enzymes are investigated by in silico methods. As evident by extra-precision docking and binding free energy calculation (MM-GBSA) results, rivoglitazone ex- hibited higher binding affinity against both ParE and MurE enzymes compared to all other selected compounds. Further molecular dynamic (MD) simulations were performed to validate the stability of rivoglitazone/4MOT and rivoglitazone/4C13 complexes and to get insight into the binding mode of inhibitor. Thus, we hypothesize that structural modifications of the rivoglitazone scaffold can be useful for the development of an effective antibacterial agent.
    [Show full text]
  • Sugar-Lowering Drugs for Type 2 Diabetes Mellitus and Metabolic Syndrome—Review of Classical and New Compounds: Part-I
    pharmaceuticals Review Sugar-Lowering Drugs for Type 2 Diabetes Mellitus and Metabolic Syndrome—Review of Classical and New Compounds: Part-I Raquel Vieira 1 , Selma B. Souto 2, Elena Sánchez-López 3,4 , Ana López Machado 4, Patricia Severino 5,6 , Sajan Jose 7 , Antonello Santini 8 , Ana Fortuna 9,10, Maria Luisa García 3,4, Amelia M. Silva 11,12 and Eliana B. Souto 1,13,* 1 Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), Pólo das Ciências da Saúde, 3000-548 Coimbra, Portugal; [email protected] 2 Department of Endocrinology, Hospital São João, Prof. Alameda Hernâni Monteiro, 4200-319 Porto, Portugal; [email protected] 3 Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Institute of Nanoscience and Nanotechnology (IN2UB), 08028 Barcelona, Spain; [email protected] (E.S.-L.); [email protected] (M.L.G.) 4 Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), University of Barcelona, 08028 Barcelona, Spain; [email protected] 5 Laboratory of Nanotechnology and Nanomedicine (LNMED), Institute of Technology and Research (ITP), Av. Murilo Dantas, 300, Aracaju 49010-390, Brazil; [email protected] 6 University of Tiradentes (UNIT), Industrial Biotechnology Program, Av. Murilo Dantas 300, Aracaju 49032-490, Brazil 7 Department of Pharmaceutical Sciences, Mahatma Gandhi University, Cheruvandoor Campus, Ettumanoor, Kerala 686631, India; [email protected] 8
    [Show full text]
  • Endothelin Receptor Antagonists (ERA) in Hypertension and Chronic Kidney Disease: a Rose with Many Thorns Michael N
    Himmelfarb Health Sciences Library, The George Washington University Health Sciences Research Commons Medicine Faculty Publications Medicine 2013 Endothelin receptor antagonists (ERA) in hypertension and chronic kidney disease: A rose with many thorns Michael N. Doumas George Washington University V. Athyros Aristotle University of Thessaloniki N. Katsiki Aristotle University of Thessaloniki A. Reklou Aristotle University of Thessaloniki A. Lazaridis Aristotle University of Thessaloniki See next page for additional authors Follow this and additional works at: http://hsrc.himmelfarb.gwu.edu/smhs_medicine_facpubs Part of the Medicine and Health Sciences Commons Recommended Citation Doumas, M., Athyros, V., Katsiki, N., Reklou,A., Lazaridis, A., Karagiannis, A. (2013). Endothelin receptor antagonists (ERA) in hypertension and chronic kidney disease: A rose with many thorns. Open Hypertension Journal, 5, 12-17. This Journal Article is brought to you for free and open access by the Medicine at Health Sciences Research Commons. It has been accepted for inclusion in Medicine Faculty Publications by an authorized administrator of Health Sciences Research Commons. For more information, please contact [email protected]. Authors Michael N. Doumas, V. Athyros, N. Katsiki, A. Reklou, A. Lazaridis, and A. Karagiannis This journal article is available at Health Sciences Research Commons: http://hsrc.himmelfarb.gwu.edu/smhs_medicine_facpubs/ 322 Send Orders for Reprints to [email protected] 12 The Open Hypertension Journal, 2013, 5, 12-17 Open Access Endothelin Receptor Antagonists (ERA) in Hypertension and Chronic Kidney Disease: a Rose with Many Thorns Doumas M1,2,*, Athyros V1, Katsiki N1, Reklou A1, Lazaridis A1 and Karagiannis A1 12nd Propedeutic Department of Internal Medicine, Aristotle University, Thessaloniki, Greece 2VAMC and George Washington University, Washington, DC, USA Abstract: The discovery of endothelin created a lot of enthusiasm and paved new therapeutic avenues for the treatment of arterial hypertension.
    [Show full text]
  • A Novel JAK1 Mutant Breast Implant-Associated Anaplastic Large Cell Lymphoma Patient-Derived Xenograft Fostering Pre- Clinical Discoveries
    Cancers 2019 S1 of S18 Supplementary Materials: A Novel JAK1 Mutant Breast Implant-Associated Anaplastic Large Cell Lymphoma Patient-Derived Xenograft Fostering Pre- Clinical Discoveries Danilo Fiore, Luca Vincenzo Cappelli, Paul Zumbo, Jude M. Phillip, Zhaoqi Liu, Shuhua Cheng, Liron Yoffe, Paola Ghione, Federica Di Maggio, Ahmet Dogan, Inna Khodos, Elisa de Stanchina, Joseph Casano, Clarisse Kayembe, Wayne Tam, Doron Betel, Robin Foa’, Leandro Cerchietti, Raul Rabadan, Steven Horwitz, David M. Weinstock and Giorgio Inghirami A B C Figure S1. (A) Histology micrografts on IL89 PDTX show overall similarity between T1 T3 and T7 passages (upper panels). Immunohistochemical stains with the indicated antibodies (anti-CD3, anti- CD25 and anti-CD8 [x20]) (lower panels). (B) Flow cytometry panel comprehensive of the most represented surface T-cell lymphoma markers, including: CD2, CD3, CD4, CD5, CD8, CD16, CD25, CD30, CD56, TCRab, TCRgd. IL89 PDTX passage T3 is here depicted for illustration purposes. (C) Analysis of the TCR gamma specific rearrangement clonality in IL89 diagnostic sample and correspondent PDTX after 1 and 5 passages (T1 and T5). A WT Primary p.G1097D IL89 T1 p.G1097D IL89 T5 p.G1097D IL89 cell line B Figure S2. (A) Sanger sequencing confirms the presence of the JAK1 p.G1097D mutation in IL89 PDTX samples and in the cell line, but the mutation is undetectable in the primary due to the low sensitivity of the technique. (B) Manual backtracking of mutations in the primary tumor using deep sequencing data allowed for the identification of several hits at a very low VAF compared to the PDTX-T5. A B IL89 CTRL 30 CTRL Ruxoli?nib S 20 M Ruxoli?nib A R G 10 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 1 1 1 1 1 WEEKS AFTER ENGRAFTMENT Figure S3.
    [Show full text]