Download PDF
Thromb Haemost 2010; 104(01): 1-3
DOI: 10.1160/TH10-04-0256
Editorial Focus
Schattauer GmbH

Obstacles and options in the quest for drug candidates against vascular disease

Christian Weber   *
1   Institute for Molecular Cardiovascular Research – IMCAR, RWTH Aachen University, Aachen Germany
2   Cardiovascular Research Institute Maastricht – CARIM, Maastricht, The Netherlands
› Author Affiliations
Further Information

Publication History

Received: 28 April 2010

Accepted after minor revision: 14 May 2010

Publication Date:
23 November 2017 (online)

  PDF Download  Permissions and Reprints

Summary

he difficulties in cardiovascular drug development have been exposed by recent clinical trials, which have uncovered various limitations of promising drug candidates. Yet, the imperative to improve medical treatment of atherosclerosis in aging populations afflicted by metabolic disease remains unbroken. Herein alternatives to metabolically active compounds such as glitazones and torcetrapib are introduced and discussed, namely CC chemokine receptor 5 (CCR5) antagonists recently approved for treatment of patients with human immunodeficiency virus-1, interceptors of proatherogenic chemokine interactions, and actively protective pathways. A combination of different strategies may yield improved safety profiles of these therapeutics.

Keywords

Atherosclerosis - chemokines - drug design

* Disclosure: Dr. Christian Weber is shareholder of Carolus Therapeutics Inc.


 

  • References

  • 1 Ridker PM, Danielson E, Fonseca FA. et al. JUPITER Trial Study Group. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009; 373: 1175-1182.
    CrossrefPubMedGoogle Scholar
  • 2 Home PD, Pocock SJ, Beck-Nielsen H. et al. RECORD Study Team Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 2009; 373: 2125-2135.
    CrossrefPubMedGoogle Scholar
  • 3 Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356: 2457-2471.
    CrossrefPubMedGoogle Scholar
  • 4 Nissen SE. Setting the RECORD Straight. J Am Med Assoc 2010; 303: 1194-1195.
    CrossrefPubMedGoogle Scholar
  • 5 Lincoff AM, Wolski K, Nicholls SJ. et al. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. J Am Med Assoc 2007; 298: 1180-1188.
    CrossrefPubMedGoogle Scholar
  • 6 Nissen SE, Nicholls SJ, Wolski K. et al. STRADIVARIUS Investigators. Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. J Am Med Assoc 2008; 299: 1547-1560.
    CrossrefPubMedGoogle Scholar
  • 7 Nissen SE, Tardif JC, Nicholls SJ. et al. ILLUSTRATE Investigators. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007; 356: 1304-1316.
    CrossrefPubMedGoogle Scholar
  • 8 Nicholls SJ, Tuzcu EM, Brennan DM. et al. Cholesteryl ester transfer protein inhibition, high-density lipoprotein raising, and progression of coronary atherosclerosis: insights from ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation). Circulation 2008; 118: 2506-2514.
    CrossrefPubMedGoogle Scholar
  • 9 BARI 2D Study Group Frye RL, August P, et al.. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009; 360: 2503-2515.
    CrossrefPubMedGoogle Scholar
  • 10 Koenen RR, Weber C. Therapeutic targeting of chemokine interactions in atherosclerosis. Nat Rev Drug Discov 2010; 09: 141-153.
    CrossrefPubMedGoogle Scholar
  • 11 Braunersreuther V, Zernecke A, Arnaud C. et al. Ccr5 but not Ccr1 deficiency reduces development of diet-induced atherosclerosis in mice. Arterioscler Thromb Vasc Biol 2007; 27: 373-379.
    PubMedGoogle Scholar
  • 12 Gulick RM, Lalezari J, Goodrich J. et al. MOTIVATE Study Teams. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med 2008; 359: 1429-1441.
    CrossrefPubMedGoogle Scholar
  • 13 Fätkenheuer G, Nelson M, Lazzarin A. et al. MOTIVATE 1 and MOTIVATE 2 Study Teams. Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection. N Engl J Med 2008; 359: 1442-1455.
    CrossrefPubMedGoogle Scholar
  • 14 Kuritzkes DR. HIV-1 entry inhibitors: an overview. Curr Opin HIV AIDS 2009; 04: 82-87.
    CrossrefPubMedGoogle Scholar
  • 15 Hsue PY, Hunt PW, Schnell A, et al.. Role of viral replication, antiretroviral therapy, and immunodeficiency in HIV-associated atherosclerosis. AIDS 2009; 23: 1059-1067.
    CrossrefPubMedGoogle Scholar
  • 16 Weber C. Killing two birds with one stone: targeting chemokine receptors in atherosclerosis and HIV infection. Arterioscler Thromb Vasc Biol 2005; 25: 2448-2450.
    CrossrefPubMedGoogle Scholar
  • 17 Glass WG, McDermott DH, Lim JK. et al. CCR5 deficiency increases risk of symptomatic West Nile virus infection. J Exp Med 2006; 203: 35-40.
    CrossrefPubMedGoogle Scholar
  • 18 Koenen RR, von Hundelshausen P, Nesmelova IV. et al. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice. Nat Med 2009; 15: 97-103.
    CrossrefPubMedGoogle Scholar
  • 19 Weber C, Koenen RR. Fine-tuning leukocyte responses: towards a chemokine 'interactome'. Trends Immunol 2006; 27: 268-273.
    CrossrefPubMedGoogle Scholar
  • 20 von Hundelshausen P, Koenen RR, Sack M. et al. Heterophilic interactions of platelet factor 4 and RANTES promote monocyte arrest on endothelium. Blood 2005; 105: 924-930.
    PubMedGoogle Scholar
  • 21 Damås JK, Waehre T, Yndestad A. et al. Stromal cell-derived factor-1alpha in unstable angina: potential antiinflammatory and matrix-stabilizing effects. Circulation 2002; 106: 36-42.
    CrossrefPubMedGoogle Scholar
  • 22 Zernecke A, Bot I, Djalali-Talab Y. et al. Protective role of CXC receptor 4/CXC lig-and 12 unveils the importance of neutrophils in atherosclerosis. Circ Res 2008; 102: 209-217.
    CrossrefPubMedGoogle Scholar
  • 23 Schroeter MR, Humboldt T, Schäfer K. et al. Rosuvastatin reduces atherosclerotic lesions and promotes progenitor cell mobilisation and recruitment in apolipo-protein E knockout mice. Atherosclerosis 2009; 205: 63-73.
    CrossrefPubMedGoogle Scholar
  • 24 Zernecke A, Bidzhekov K, Noels H. et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci Signal 2009; 02: ra81.
    PubMedGoogle Scholar
  • 25 Stellos K, Bigalke B, Langer H. et al. Expression of stromal-cell-derived factor-1 on circulating platelets is increased in patients with acute coronary syndrome and correlates with the number of CD34+ progenitor cells. Eur Heart J 2009; 30: 584-593.
    CrossrefPubMedGoogle Scholar
  • 26 Corson MA. Phospholipase A2 inhibitors in atherosclerosis: the race is on. Lancet 2009; 373: 608-610.
    CrossrefPubMedGoogle Scholar
  • 27 Jennings LK. Mechanisms of platelet activation: need for new strategies to protect against platelet-mediated atherothrombosis. Thromb Haemost 2009; 102: 248-257.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Steffens S, Montecucco F, Mach F. The inflammatory response as a target to reduce myocardial ischaemia and reperfusion injury. Thromb Haemost 2009; 102: 240-247.
    Article in Thieme ConnectPubMedGoogle Scholar