Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclohexadiene having atoms double bonded directly at the 1-...
Reexamination Certificate
2000-05-01
2002-02-12
Pryor, Alton (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclohexadiene having atoms double bonded directly at the 1-...
C552S296000
Reexamination Certificate
active
06346634
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds suitable for use in the treatment of heart disease. These compounds do not suffer from the problem of patient tolerance that is associated with the use of conventional agents such as organic nitrates.
BACKGROUND OF THE INVENTION
Organic nitrates and nitrites have been widely prescribed for the prophylactic treatment of angina for over 100 years. More recently, these drugs have been extended to manage coronary artery disease, acute myocardial infarction and congestive heart failure (Parker & Parker, (1998)
N. Engl. J. Med
. 338; 520-531). Examples of such drugs include glyceryl trinitrate (GTN), 1,2-glyceryl dinitrate, 1,3-glyceryl dinitrate, isosorbide dinitrate, isosorbide-2-mononitrate and isosorbide-5-mononitrate.
The primary action of organic nitrates is vasodilation, which is attributable primarily to nitrate-induced relaxation of vascular smooth muscle in veins, arteries, and arterioles. Organic nitrates are converted in the body to endothelium-derived relaxing factors (EDRFs), which act to dilate vascular smooth muscle and to inhibit platelet aggregation by activating guanylyl cyclase and increasing intracellular cyclic-3′,5′-guanosine monophosphate (cGMP). This represents the cellular basis for the vasodilatory action of organic nitrates.
Organic nitrate administration has been used as a means of providing an exogenous source of EDRF that may help replenish or restore endogenous EDRF levels that are usually impaired in patients with coronary artery diseases such as atherosclerosis.
Discovered to be an EDRF, nitric oxide (NO) is an important endogenous modulator of vascular tone (Ignarro et al., (1987)
Proc. Natl. Acad Sci U.S.A
. 84:9265-9269; Palmer et al, (1987)
Nature
327:524-526). A great deal of interest has been shown in the in vivo metabolism of organic nitrates to produce NO. However, the cellular mode of action of organic nitrates, in particular, the details of nitrate to NO bio-transformation, still remain unclear. It has been suggested that bio-transformation of organic nitrates to NO is a thiol-dependent enzymatic denitration process catalyzed by glutathione-s-transferase and the cytochrome P450-NADPH cytochrome P450 reductase system (Bennette et al., (1994)
Trends Pharmaciol. Sci
. 15; 245-249). However, it has since been discovered that glutathione-s-transferase catalyzes the reduction of organic nitrate to nitrite, and does not catalyze the reduction of nitrite to NO.
The major problem with nitrate therapy is the rapid development of tolerance and cross-tolerance during repeated dosing with these agents (Parker & Parker, 1998). Clinically, intermittent dosing regimens that allow for a drug-free interval represent the only practical and effective strategy for avoiding nitrate tolerance. Clearly, the need to interrupt drug administration regularly reduces the effectiveness of this form of therapy.
Nitrate tolerance is believed to be a complex multi-factorial phenomenon, and the underlying mechanism of organic nitrate tolerance is poorly understood. One possible route of nitrate tolerance is due to a relative depletion of sulfhydryl groups required for bio-conversion of organic nitrates to NO. More recently it has been suggested that enhanced vascular superoxide production from endothelium plays an important role in this phenomenon (Munzel et al., (1995)
J. Clin. Invest
. 95:187-194; Rajagopalan et al, (1996)
J. Clin. Invest
. 97:1916-1923).
There thus remains a great need for compounds that are effective in the body as vasodilators and which may be administered continuously for a sustained period of time without suffering a reduction in efficacy due to development of patient tolerance.
SUMMARY OF THE INVENTION
According to the present invention there is provided a compound comprising a scavenger of superoxide and an organic nitrate or nitrite moiety. Such compounds are effective vasodilators, yet do not exhibit the problems of patient tolerance to nitrates, from which conventional vasodilatory agents suffer.
BRIEF DESCRIPTION OF THE DRAWINGS
The Figure shows a reaction scheme for preparing a superoxide scavenger-organic nitrate ester.
DETAILED DESCRIPTION OF THE INVENTION
The advance that led to the development of the compounds of the invention is based on the inventors' observation of a novel molecular mechanism of the bio-conversion of organic nitrate to NO by xanthine oxidase (XO). The XO enzyme is a homodimer of 150 kDa subunits, and contains four oxidation and reduction centers, one molybdenum cofactor, one flavin adenine dinucleotide (FAD) and two [Fe
2
S
2
] clusters. XO catalyzes the oxidative hydroxylation of a range of aromatic heterocyclic compounds of which the most notable are hypoxanthine and xanihine. During the process of purine metabolism, XO catalyzes the two-step oxidation of hypoxanthine, through xanthine, to uric acid. The oxidation of hypoxanthine or xanthine is concomitantly accompanied by the reduction of oxygen to form superoxide and H
2
O
2
(see Table 1, reaction scheme I).
TABLE 1
Reactions catalyzed by XO
Xanthine oxidase
XH + H
2
O + O
2
→ X = O + H
2
O
2
+ O
2
•−
I
activity
NADH oxidase
2NADH + 2O
2
→ NAD + O
2
•−
+ H
2
O
2
II
activity
Nitrate reductase
2NO
3
−
→ NO
2
•
+ O
2
III
activity
Nitrite reductase
2NADH + 2NO
2
•
→ 2NAD + H
2
O
2
+ 2NO
•
IV
activity
Despite being a reducing agent that is itself capable of causing significant damage to biomolecules, such as by initiating lipid peroxidation, superoxide is considered to be the most important source of oxidative stress. It can be rapidly converted to the highly toxic hydroxyl radical via the Fenton reaction or the Haber-Weiss reaction. It can also react rapidly with NO to form deleterious diffusion-controlled peroxynitrate (Beckman et al., (1990)
Proc. Natl. Acad Sci. U.S.A
. 87;1620-1624). Both hydroxyl radicals and peroxynitrate have been shown to initiate lipid peroxidation, protein and enzyme inactivation and DNA fragmentation. On this basis, the classical pathway of superoxide production by XO (see Table 1, reaction scheme I) has been implicated as constituting a major role in a number of pathogenic conditions, such as atherosclerosis, hypercholesterolaemia, diabetes mellitus and rheumatoid arthritis.
In particular, the role of XO in the generation of excess superoxide during hypoxic reperfusion injury has received a great deal of attention (McCord J. M. (1985)
N. Engl. J. Med
. 312:159-163). During ischaemia, endogenous xanthine dehydrogenase is converted to XO. Concomitantly, hypoxanthine and xanthine are accumulated as a consequence of ATP breakdown. The reperfusion phase following ischaemia allows the XO to use accumulated hypoxanthine or xanthine together with oxygen to produce a burst of tissue-damaging superoxide and H
2
O
2
.
In addition to the above-described classical reaction of XO, early studies have shown that XO can use NADH as a reducing substrate, possibly binding at a site different from that at which xanthine binds. However, this NADH oxidase activity of XO is not generally recognized and has been little studied over the years.
Several recent studies have suggested that endothelium and vascular smooth muscle contain membrane-bound NADH oxidase enzymes that use NADH as a substrate to produce superoxide (Sanders et al., (1997)
Eur. J. Biochem
. 289:523-527). The inventors' previous research and that of others has demonstrated that human XO can use not only hypoxanthine or xanthine (Table 1, reaction scheme I) but also NADH (Table 1, reaction scheme II) as a substrate to generate superoxide (Zhang et al., (1998)
Free Rad. Res
. 28;151-164).
This NADH-oxidizing activity of XO is blocked by diphenyleneiodonium (DPI) but is not suppressible by the conventional xanthine-based inhibitors, such as allopurinol, oxypurinol, BOF-4272 and Amfiutizole. Therefore, apart from the xanthine-based free radical-generating pathway
Imaizumi Atsushi
Naughton Declan P.
Sumi Yoshihiko
Zhang Zhi
Pryor Alton
Sughrue Mion Zinn Macpeak & Seas, PLLC
Teijin Limited
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