Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-09-16
2003-02-25
Low, Christopher S. F. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C530S317000, C530S324000, C530S327000, C435S069100
Reexamination Certificate
active
06525022
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to synthetic peptides having diuretic, natriuretic, and/or vasodilatory activity in mammals. The peptides of this invention are related to atrial natriuretic peptide (ANP) but exhibit decreased binding affinity to the natriuretic peptide clearance receptor (NPR-C) and improved stability toward peptidases (“enkephalinase”) known to hydrolyze natriuretic peptides.
BACKGROUND OF THE INVENTION
Maintenance of normal extracellular fluid volume depends primarily on the excretion of sodium (natriuresis) and water (diuresis) by the kidneys. These are, in turn, primarily determined by (1) the rate at which plasma is filtered at the glomerulus (glomerular filtration rate, or GFR) and (2) the degree to which sodium is actively reabsorbed along the renal tubule (with water presumably following passively). Sodium reabsorbtion is regulated, in part, by the adrenal steroid hormone aldosterone, in part by blood pressure, hematocrit and plasma viscosity and in part by various atrial natriuretic factors (ANF's) or hormones (deBold, A. J. et al.,
Life Sciences
28:89-94 [1981]; Garcia R.,
Experientia
38:1071-73 [1982]; Currie, M. S. et al.
Science
221:71-73 [1983]; Flynn T. G. et al.,
Biochem. Biophys. Res. Commun.
117:859-865 [1983]; Currie, M. G. et al.,
Science
223:67-69 [1984]; and Kanagawa, K. et al.,
Biochem. Biophys. Res. Commun.
118:131-139 [1984]).
Atrial natriuretic factors are released as a result of sensors in the atrium responsible for detecting extracellular fluid volume. It is believed that an increase in extracellular fluid volume is detected by these sensors as the atrium stretches to accommodate the increased venous return volume. In response to this stimulus ANF is released into the blood stream where it is transported to the kidney. Binding of ANF to a specific natriuretic peptide receptor (hNPR-A) in the kidney causes inhibition of sodium reabsorbtion along the renal tubule decreasing the reabsorption of water and lowering the extracellular fluid volume.
ANF is also known to be a hypotensive hormone that antagonizes various hypertensive systems including; stimulation of vasodialation, inhibition of aldosterone secretion from the adrenal gland, renin secretion from the kidney, and the renin-angiotensin II system.
It is known that the serum half-life of ANF's and related peptides (see
FIG. 1
) that act as hypotensive regulators is relatively short (Crozier, I. G. et al.,
The Lancet II
1242-1245 [1986]) and that these peptides are removed from the blood stream by several mechanisms (FIG.
2
). In addition to glomerular filtration two other distinct pathways have been identified which appear to significantly contribute to ANF clearance.
The first of these pathways involves receptor mediated ANF clearance. This pathway is reported to have sufficient capacity to account for about 70-80% of total ANF clearance from the blood stream (Maack, T., et al,
Science
238:675-678 [1987], EPO Publication No. 233,143). The human natriuretic peptide receptor (hNPR-C) responsible for this clearance is present in many tissues, especially kidney (Luft, F. C. et al.,
J. Pharmacol. Exp. Ther.
236:416-418 [1986]), and promiscuously (Bovy, P. R.,
Med. Res. Rev.
10:1156 [1990]) binds various human natriuretic peptides including hANP, hBNP, and hCNP (FIG.
3
). Various synthetic peptides, especially linear peptides (Olins, G. M., et al.,
J. Biol. Chem.
263:10989-10993 [1988]), capable of binding the hNPR-C have been described in the patent literature to enhance the natriuretic, diuretic and vasodilatation activity of endogenous ANF. Therapeutic use of these clearance receptor inhibitors presumably elevates the concentration and thus activity of all hormone peptides cleared by hNPR-C.
A second nonsaturatable clearance pathway also operates to remove serum ANF and is believed to involve the activity of a peptidase, neutral endopeptidase 24.11 (EC 3.4.24.11), also known as “enkephalinase” and referred to herein as NEP (Stevenson, S. L., et al.,
Biochem.
243L183-187 [1987]; Olins, G. M., et al.,
Biochim Biophys Acta
901:97-100 [1987]; Koehn, J. A. et al.,
J. Biol. Chem.
262:11623-11627 [1987]; Yandle, T., et al.,
Biochem Biophys Res. Commun.
146:832-839 [1987]). NEP is present in relatively high amounts in the kidney (Sonnenberg, J. L. et al.,
Peptides
9:173-180 [1988]) and is known to hydrolyze the Cys
7
-Phe
8
amide bond of ANF's (Tamburine, P. P., et al.,
J. Pharm. Exp. Ther.
251:956-961 [1989]).
It has been observed that inhibitors of NEP, such as thiophan, potentiate the biological responses of administered ANP (Fennell, S. A., et al.,
FASEB J
2:A936 [1988]); Seymour A. A. et al., ibid; Trapani, A. J., et al., ibid; McMartin, C., et al., ibid; Simmerman, M. B. et al. ibid A937). However, administration of nonpeptidyl inhibitors of this pathway, like thiorphan, has the disadvantage that the cerebral NEP or endopeptidase 24.11 (“enkephalinase”) will also be inhibited because thiorphan is capable of crossing the blood-brain barrier (Bourgoin, S. et al.,
J. Pharm. Exp. Ther.
238:360-366 (1986). In addition to the use of thiorphan, a variety of other strategies for the inhibition of NEP have been described. These strategies include the use of a metal binding substituent appropriately spaced from the aromatic Phe
8
moiety of ANF. Roques., E. P., et al.,
Nature
288:286-288 (1980); see also Gordon, E. M., et al.,
Life Sci
33 (Supplement 1): 113-116 (1983); Mumford, R. M., et al.,
Biochem Biophys. Res. Comm.
109:1303-1309 (1982); Fournie-Zaluski, M. C., et al.,
J. Med. Chem.
26:60-65 (1983); Waksman, G., et al.,
Biochem. Biophys. Res. Comm.
131:262-268 (1985); U.S. Pat. No. 5,248,764. Other strategies also include substitution of unnatural residues for Phe
8
such as cyclohexylamine (
Fed. Proc.,
45:657 [1986]; U.S. Pat. Nos. 5,106,834 and 4,861,755) or N-alkylated amino acids like N-Me-Phe (Nutt et al., EPA 0 465 097). Introduction of D amino acids such as D-Cys or D-Ala has been described (Nutt R. and Veber, D. F.
Endocrin. Metab, Clin. N. Am.,
16:19-41 [1988]; U.S. Pat. No. 4,816,443) and replacement of amide bonds is described generally be Lewicki et al., U.S. Pat. No. 4,935,492 (see also U.S. Pat. No. 5,095,004).
Because of the obvious therapeutic potential of natriuretic peptides and variants thereof in the treatment of congestive heart failure, hypertension, acute kidney failure etc., numerous synthetic ANF's have been prepared that mimic the biological activity of wild-type ANF but are reported to have improved stability, potency, or duration of action when compared to wild-type ANF. Many of these synthetic ANF's are disclosed in the following U.S. Pat. Nos.: 4,496,544; 4,496,544; 4,609,725; 4,673,732; 4,716,147; 4,757,048; 4,764,504; 4,804,650; 4,816,443; 4,861,755; 4,935,492; 4,952,561; 5,057,495; 5,057,603; 5,091,366; 5,095,004; 5,106,834; 5,159,061; 5,204,328; and 5,212,286. In addition, various foriegn documents describing ANF analogs include: WO85/04870; WO85/04872; WO88/03537; WO88/06596; WO89/10935; WO89/05654; WO90/01940; WO90/14362; WO92/06998; EPA 0 323 740; EPA 0 356 124; EPA 0 291 999; EPA 0 350 318; EPA 0 497 368; EPA 0 385 476; and EPA 0 341 603. None of these publications disclose a hANF variant having human receptor specificity (i.e. high affinity for hNPR-A and low affinity for hNPR-C), nor do they disclose the substitutions to hANF(1-28) residues 9, 11, or 16 necessary to achieve this selectivity. Only WO88/03537 discloses a positively charged residue, D-Arg, at position 16 in a truncated form of ANF.
OBJECTS OF THE INVENTION
It is an object of this invention to provide novel compounds having biological activity like hANF(1-28) but with enhanced metabolic stability. It is another object of this invention to provide novel peptides or peptidomimetic compounds having pot
Burnier John P.
Cunningham Brian C.
Lowe David G.
McDowell Robert S.
Oare David
Genentech Inc.
Gupta Anish
Low Christopher S. F.
Merchant & Gould P.C.
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