Novel approach towards NO-free activators of sGC enzyme for medical treatment of heart diseases

Cardiac patients learn very quickly and very well their symptoms and can easily assimilate the treatment and remember it. Nitroglycerin and its analogs are used as medicines for angina pectoris and heart failure.1,2 Doctors prescribe it and teach the patients that it should be taken only in case they feel an approaching angina attack. However many clinical studies, both of patients with angina pectoris and of patients with heart failure have demonstrated that continuous administration of organic nitrates leads to the development of nitroglycerine tolerance and decrease of its therapeutic efficiency.3 It is the goal of this project to design and prepare new NO-free functional mimics.

Nitro-compounds are used in heart diseases because of its vasodilatative property. Nitroglycerin and isosorbide nitrites dilate arterial blood vessels decreasing the cardiac preload and thus inducing a therapeutic effect on the cardiac muscle.4 It is established that after being absorbed the medicine is converted into nitric oxide. This molecule is known to be involved in the control of blood pressure, neurotransmission, and the immunedefense system of the body.5 NO activates soluble guanylyl cycles (sGC),6 which catalyses the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP), which triggers further biochemical effects that ultimately result in a physiological response (Scheme 1).7,8,9,10 Another mechanism of high-output sGC activation was described early on by Ignarro and co-workers who reported that protoporphyrin IX (PPIX) activated efficiently the sGC enzyme.11

Scheme 1
Scheme 1.Transformation of GTP into cGMP catalyzed by sGC

It is the goal of this project to produce new functional mimics for sGC regulation. We believe that chemically modified corrin compounds or other tetrapyrroles may be even more effective regulators of sGC. To test this hypothesis we will experimentally execute the following aims:

  1. Elaborate new methods for the preparation of vitamin B12 and factor B derivatives as sGC regulators.
  2. Prepare new porphyrin (especially PPIX) derivatives.
  3. Prepare hybrid molecules with dual mode of action e.g. vitamin B12/factor B - porphyrinoid conjugates.
  4. Investigate the cellular and cardiovascular effect of sGC activation by the new corrin derivative and hybrid molecules.
  5. To assess the cellular toxicity of the new corrin derivatives and hybrid molecules.

References:

  1. L.J. Ignarro J. Physiol. Pharm. 2002, 53, 503 - 514.
  2. L.J. Ignarro, C. Napoli, J. Loscalzo Circ. Res. 2002, 90, 21 - 28.
  3. S. Ghio, S. de Servi, R. Perotti, E. Eleuteri, C. Montemartini, G. Specchia Circulation 1992, 86, 798 - 802.
  4. L.J. Ignarro Proc. Natl. Acad. Sci. USA 2002, 99, 7816 - 7817.
  5. L.I. Ingarro, C. Napoli Nitric Oxide: Biol. Chem. 2001, 5, 88 - 97.
  6. A. Pyriochou, A. Papapetropoulos Cellular signaling 2005, 17, 407 _ 413.
  7. W.P. Arnold, C.K. Mittal, S. Katsuki, F. Murad Proc. Natl. Acad. Sci. USA 1977, 74, 3203 - 3207.
  8. Z. Chen, J. Zhang, J.S. Stamler Proc. Natl. Acad. Sci. USA 2002, 99, 8306 - 8311.
  9. L.J. Ignarro, H., Lippton, J.C. Edwards, W.H. Baricos, A.L. Hyman, P.J. Kadowitz, C.A. Gruetter J. Pharmacol. Exp. Ther. 1981, 218, 739 - 749.
  10. F. Murad, C.K. Mittal, W.P. Arnod,S. Katsuki, H. Kimura Adv. Cyclic Nucleotide Res. 1978, 9, 145 - 158.
  11. M.S. Wolin, K.S. Wood, L.J. Ignarro J. Biol. Chem. 1982, 257, 13312 - 13320.