Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus esters
Reexamination Certificate
1998-09-03
2002-05-07
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus esters
C558S200000, C558S201000, C562S809000, C564S012000, C206S569000, C514S137000
Reexamination Certificate
active
06384261
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the compounds that modulate the activity of the endothelin family of peptides. In particular, phosphoramidate compounds, phosphinic amide compounds and related compounds and use of these compounds as endothelin antagonists are provided.
BACKGROUND OF THE INVENTION
The vascular endothelium releases a variety of vasoactive substances, including the endothelium-derived vasoconstrictor peptide, endothelin (ET) (see, e.g., Vanhoutte et al. (1986)
Annual Rev. Physiol
. 48: 307-320; Furchgott and Zawadski (1980)
Nature
288: 373-376). Endothelin, which was originally identified in the culture supernatant of porcine aortic endothelial cells (see, Yanagisawa et al. (1 988)
Nature
332: 411-415), is a potent twenty-one amino acid peptide vasoconstrictor. It is the most potent vasopressor known and is produced by numerous cell types, including the cells of the endothelium, trachea, kidney and brain. Endothelin is synthesized as a two hundred and three amino acid precursor preproendothelin that contains a signal sequence which is cleaved by an endogenous protease to produce a thirty-eight (human) or thirty-nine (porcine) amino acid peptide. This intermediate, referred to as big endothelin, is processed in vivo to the mature biologically active form by a putative endothelin-converting enzyme (ECE) that appears to be a metal-dependent neutral protease (see, e.g., Kashiwabara et al. (1989)
FEBS Lttrs
. 247: 337-340). Cleavage is required for induction of physiological responses (see, e.g., von Geldern et al. (1991)
Peptide Res
. 4: 32-35). In porcine aortic endothelial cells, the thirty-nine amino acid intermediate, big endothelin, is hydrolyzed at the Trp
21
-Val
22
bond to generate endothelin-1 and a C-terminal fragment. A similar cleavage occurs in human cells from a thirty-eight amino acid intermediate. Three distinct endothelin isopeptides that exhibit potent vasoconstrictor activity have been identified. They are endothelin-1, endothelin-2 and endothelin-3.
The isopeptides are encoded by a family of three genes (see, e.g., Inoue et al. (1989)
Proc. Natl. Acad. Sci. USA
86: 2863-2867; see, also Saida et al. (1989)
J. Biol. Chem
. 264: 14613-14616). The nucleotide sequences of the three human genes are highly conserved within the region encoding the mature 21 amino acid peptides and the C-terminal portions of the peptides are identical. Endothelin-2 is (Trp
6
,Leu
7
) endothelin-1 and endothelin-3 is (Thr
2
,Phe
4
,Thr
5
,Tyr
6
, Lys
7
,Tyr
14
) endothelin-1. The endothelin peptides exhibit numerous biological activities in vitro and in vivo. Endothelin provokes a strong and sustained vasoconstriction in vivo in rats and in isolated vascular smooth muscle preparations; it also provokes the release of eicosanoids and endothelium-derived relaxing factor (EDRF) from perfused vascular beds. Intravenous administration of endothelin-1 and in vitro addition to vascular and other smooth muscle tissues produce long-lasting pressor effects and contraction, respectively (see, e.g., Bolger et al. (1991)
Can. J. Physiol. Pharmacol
. 69: 406-413). In isolated vascular strips, for example, endothelin-1 is a potent (EC
50
=4×10
−10
M), slow acting, but persistent, contractile agent. A single dose in vivo elevates blood pressure in about twenty to thirty minutes. Endothelin-induced vasoconstriction is not affected by antagonists to known neurotransmitters or hormonal factors, but is abolished by calcium channel antagonists. The effect of calcium channel antagonists, however, is most likely the result of inhibition of calcium influx, since calcium influx appears to be required for the long-lasting contractile response to endothelin.
Endothelin also mediates renin release, stimulates ANP release and induces a positive inotropic action in guinea pig atria. In the lung, endothelin-1 acts as a potent bronchoconstrictor (Maggi et al. (1989)
Eur. J. Pharmacol
. 160: 179-182). Endothelin increases renal vascular resistance, decreases renal blood flow, and decreases glomerular filtrate rate. It is a potent mitogen for glomerular mesangial cells and invokes the phosphoinoside cascade in such cells (Simonson et al. (1990)
J. Clin. Invest
. 85: 790-797). Release of endothelins from cultured endothelial cells is modulated by a variety of chemical and physical stimuli and appears to be regulated at the level of transcription and/or translation. Expression of the gene encoding endothelin-1 is increased by chemical stimuli, including adrenaline, thrombin and Ca
2+
ionophore. The production and release of endothelin from the endothelium is stimulated by angiotensin II, vasopressin, endotoxin, cyclosporine and other factors (see, Brooks et al. (1991)
Eur. J. Pharm
. 194:115-117), and is inhibited by nitric oxide. Endothelial cells appear to secrete short-lived endothelium-derived relaxing factors (EDRF), including nitric oxide or a related substance (Palmer et al. (1987)
Nature
327: 524-526), when stimulated by vasoactive agents, such as acetylcholine and bradykinin. Endothelin-induced vasoconstriction is also attenuated by atrial natriuretic peptide (ANP).
There are specific high affinity binding sites (dissociation constants in the range of 2-6×10
−10
M) for the endothelins in the vascular system and in other tissues, including the intestine, heart, lungs, kidneys, spleen, adrenal glands and brain. Binding is not inhibited by catecholamines, vasoactive peptides, neurotoxins or calcium channel antagonists. Endothelin binds and interacts with receptor sites that are distinct from other autonomic receptors and voltage dependent calcium channels. Competitive binding studies indicate that there are multiple classes of receptors with different affinities for the endothelin isopeptides. The sarafotoxins, a group of peptide toxins from the venom of the snake
Atractaspis eingadensis
that cause severe coronary vasospasm in snake bite victims, have structural and functional homology to endothelin-1 and bind competitively to the same cardiac membrane receptors (Kloog et al. (1989)
Trends Pharmacol. Sci
. 10: 212-214).
Two distinct endothelin receptors, designated ET
A
and ET
B
, have been identified and DNA clones encoding each receptor have been isolated (Arai et al. (1990)
Nature
348: 730-732; Sakurai et al. (1990)
Nature
348: 732-735). Based on the amino acid sequences of the proteins encoded by the cloned DNA, it appears that each receptor contains seven membrane spanning domains and exhibits structural similarity to G-protein-coupled membrane proteins. Messenger RNA encoding both receptors has been detected in a variety of tissues, including heart, lung, kidney and brain. The distribution of receptor subtypes is tissue specific (Martin et al. (1989)
Biochem. Biophys. Res. Commun
. 162: 130-137). ET
A
receptors appear to be selective for endothelin-1 and are predominant in cardiovascular tissues. ET
B
receptors are predominant in noncardiovascular tissues, including the central nervous system and kidney, and interact with the three endothelin isopeptides (Sakurai et al. (1990)
Nature
348: 732-734). In addition, ET
A
receptors occur on vascular smooth muscle, are linked to vasoconstriction and have been associated with cardiovascular, renal and central nervous system diseases; whereas ET
B
receptors are located on the vascular endothelium, linked to vasodilation (Takayanagi et al. (1991)
FEBS Lttrs
. 282: 103-106) and have been associated with bronchoconstrictive disorders.
By virtue of the distribution of receptor types and the differential affinity of each isopeptide for each receptor type, the activity of the endothelin isopeptides varies in different tissues. For example, endothelin-1 inhibits
125
I-labelled endothelin-1 binding in cardiovascular tissues forty to seven hundred times more potently than endothelin-3.
125
I-labelled endothelin-1 binding in non-cardiovasculartissues, such as kidney, adrenal gland, and cerebellum, is inhibited to the same extent by endothelin-1 and endothelin-3, which i
Chan Ming Fai
Verner Erik Joel
Heller Ehrman White & McAuliffe LLP
Higel Floyd D.
Seidman Stephanie
Texas Biotechnology Corporation
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