US2002132973A1PendingUtilityA1
Peptide parathyroid hormone analogs
Priority: May 14, 1997Filed: Mar 13, 2002Published: Sep 19, 2002
Est. expiryMay 14, 2017(expired)· nominal 20-yr term from priority
A61P 3/14A61P 43/00A61P 5/18A61K 38/00C07K 14/635C07D 211/34A61P 19/00A61P 19/10
41
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Claims
Abstract
This invention is directed to cyclic analogs of hPTH(1-34) and hPTHrP(1-34), to pharmaceutical compositions comprising these peptide compounds, and to a method of treating diseases associated with calcium regulation in the body.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A cyclic peptide compound of formula
X-A 10 -A 11 -A 12 -A 13 -A 14 -A 15 -A 16 -A 17 -A 18 -A 19 -A 20 -A 21 -A 22 -A 23 -A 24 A 25 -A 26 -A 27 -Y
or a pharmaceutically acceptable salt or prodrug thereof wherein
X is selected from the group consisting of
(a) R 1a -A 0 -A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -,
(b) R 1a -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -,
(c) R 1b -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -,
(d) R 1a -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -,
(e) R 1a -A 5 -A 6 -A 7 -A 8 -A 9 -,
(f) R 1a -A 6 -A 7 -A 8 -A 9 -,
(g) R 1a -A 7 -A 8 -A 9 -,
(h) R 1a -A 8 -A 9 -,
(i) R 1a -A 9 -, and
(j) R 1a -;
Y is selected from the group consisting of
(a) -R 3 ,
(b) -A 28 -R 3 ,
(c) -A 28 -A 29 -R 3 ,
(d) -A 28 -A 29 -A 30 -R 3 ,
(e) -A 28 -A 29 -A 30 -A 31 -R 3 ,
(f) -A 28 -A 29 -A 30 -A 31 -A 32 -R 3 ,
(g) -A 18 -A 29 -A 30 -A 31 -A 32 -A 33 -R 3 , and
(h) -A 28 -A 29 -A 30 -A 31 -A 32 -A 33 -A 34 -R 3 ;
R 1a is H, alkyl, aralkyl or —COR 2 ;
R 1b is R 1a or a group of formula
R 2 is alkyl, alkenyl, alkynyl, aryl or aralkyl;
R 3 is a group of formula A 35 -OR 4 or A 35 -NR 4 R 5 ;
R 4 and R 5 are independently H or lower alkyl;
R 6 and R 9 are independently H or alkyl;
R 7 is alkyl;
R 8 is H, alkyl or COR 2 ;
R 10 is H or halogen;
R 11 is alkyl or aralkyl;
m is 1, 2 or 3;
n is 3 or 4;
A 0 is absent or a peptide of from one to six amino acid residues;
A 1 is Ser, Ala, Gly or D-Pro, or an equivalent amino acid thereof;
A 2 is Ala, Val or Gly, or an equivalent amino acid thereof;
A 3 is Ala, Ser, Gly or D-Pro, or an equivalent amino acid thereof;
A 4 is Glu, Ala or Gly, or an equivalent amino acid thereof;
A 5 is Ile, His, Ala or Gly, or an equivalent amino acid thereof;
A 6 is Ala, Gln, Gly or D-Pro, or an equivalent amino acid thereof;
A 7 is Ala, Leu, Gly, or an equivalent amino acid thereof;
A 8 is Leu, Nle, Gly or D-Pro, or an equivalent amino acid thereof;
A 9 is His, Ala, D-Pro or Gly, or an equivalent amino acid thereof;
A 10 is Ala, Asn, Asp, Glu, Gly or Lys;
A 11 is Ala, Gly, Leu or Lys, or an equivalent amino acid thereof;
A 12 is Ala or Gly, or an equivalent amino acid thereof;
A 13 is Ala, Gly or Lys;
A 14 is Ala, Asp, Gly, His, Lys or Ser;
A 15 is Ala, Gly, Ile, D-Pro or Leu, or an equivalent amino acid thereof;
A 16 is Asn, Ala, Gly, D-Pro or Gln, or an equivalent amino acid thereof;
A 17 is Ala, Asp, Gly, Lys or Ser;
A 18 is Asp, Leu, Lys, Orn or Nle;
A 19 is Arg or Glu, or an equivalent amino acid thereof;
A 20 is Arg or an equivalent amino acid thereof;
A 21 is Arg, Asp, Lys or Val;
A 22 is Asp, Glu, Lys, Orn or Phe;
A 23 is Leu, Phe or Trp, or an equivalent amino acid thereof;
A 24 is Leu or an equivalent amino acid thereof;
A 25 is Arg, Asp, Glu, His or Lys;
A 26 is His or Lys;
A 27 is Leu or Lys, or an equivalent amino acid thereof;
A 28 is Ile or Leu, or an equivalent amino acid thereof;.
A 29 is Ala, Asp, Glu or Gin;
A 30 is Asp, Glu or Lys;
A 31 is Ile, Leu or Val, or an equivalent amino acid thereof;
A 32 is H is, or an equivalent amino acid thereof,
A 33 is Asn or Thr, or an equivalent amino acid thereof;
A 34 is Ala or Phe, or an equivalent amino acid thereof
A 35 is absent or a peptide of from 1 to 4 amino acids; and
the side chains of at least one of the following pairs of amino acid residues, A 10 and A 14 , A 13 and A 17 , A 14 and A 18 , A 17 and A 21 , and A 18 , A 22 , and A 25 , A 25 and A 29 and A 26 and A 30 are linked through an amide bond to form a bridge, and the side chain of each of A 10 , A 13 , A 14 , A 17 , A 18 , A 21 , A 22 , A 25 , A 26 , A 29 , and A 30 contributes, at most, to the formation of a single bridge; provided that
(a) when the side chains of A 13 and A 17 are linked through an amide bond to form a bridge, then the side chains of at least one of A 18 and A 22 , A 21 and A 25 and A 25 and A 29 are also linked through an amide, ester, disulfide or lanthionine bond;
(b) that when the side chains of A 26 and A 30 are linked through an amide bond to form a bridge, then the side chains of at least one of A 10 and A 14 , A 14 and A 18 , A 17 and A 21 and A 25 are also linked through an amide bond; and
(c) that when the side chains of A 13 and A 17 and A 26 and A 30 are linked through an amide bond to form a bridge, then the side chains of A 18 and A 22 or A 21 and A 25 are also linked through an amide bond, wherein the bridge formed between the side chains of another pair of amino acid residues.
2 . A peptide compound according to claim 1 , or a pharmaceutically acceptable salt or prodrug thereof wherein R 1a is H and Y is NH 2 .
3 . A peptide compound according to claim 2 , or a pharmaceutically acceptable salt or prodrug thereof wherein X is
(a) R 1a -A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -, (b) R 1a -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 - or (c) R 1a -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -.
4 . A peptide compound according to claim 3 , or a pharmaceutically acceptable salt or prodrug thereof wherein A 1 is Ala, Gly or D-Pro; A 8 is Nle and A 27 is Leu.
5 . A peptide compound according to claim 4 , or a pharmaceutically acceptable salt or prodrug thereof wherein
(i) the side chains of A 10 and A 14 are linked through an amide bond to form a bridge; (ii) the side chains of A 14 and A 18 are linked through an amide bond to form a bridge; (iii) the side chains of A 17 and A 21 are linked through an amide bond to form a bridge; (iv) the side chains of A 18 and A 22 are linked through an amid bond to form a bridge; (v) the side chains of A 21 and A 25 are linked through an amide bond to form a bridge; or (vi) the side chains of A 25 and A 29 are linked through an amide bond to form a bridge.
6 . A peptide compound according to claim 5 , or a pharmaceutically acceptable salt or prodrug thereof wherein A 10 is Asp or Lys; A 13 is Lys; A 14 is Asp or Lys; A 17 is Asp or Ser; A 18 is Nle; A 21 is Arg or Val; A 22 is Glu or Phe; A 25 is Arg or His; A 26 is Lys or His, A 29 is Ala or Gln; and A 30 is Asp or Glu; and the side-chains of A 10 and A 14 are linked through an amide bond to form a bridge.
7 . A peptide compound according to claim 5 , or a pharmaceutically acceptable salt or prodrug thereof wherein A 10 is Asn or Asp; A 13 is Lys; A 14 is Asp or Lys; A 17 is Asp or Ser; A 18 is Nle; A 21 is Arg or Val; A 22 is Glu or Phe; A 25 is Arg or His; A 26 is His or Lys; A 29 is Ala or Gln; and A 30 is Asp or Glu; and the side chains of A 14 and A 18 are linked through an amide bond to form a bridge.
8 . A peptide compound according to claim 5 , or a pharmaceutically acceptable salt or prodrug thereof wherein A 10 is Asn or Asp; A 13 is Lys; A 14 is His or Ser; A 17 is Asp or Lys; A 18 is Nle; A 21 is Asp or Lys; A 22 is Glu or Phe; A 25 is Arg or His; A 26 is His or Lys; A 29 is Ala or Gln; and A 30 is Asp or Glu; and the side chains of A 17 and A 21 are linked through an amide bond to form a bridge.
9 . A peptide compound according to claim 5 , or a pharmaceutically acceptable salt or prodrug thereof wherein A 10 is Asn or Asp; A 13 is Lys; A 14 is His or Ser; A 17 is Asp or Ser; A 18 is Asp, Lys or Orn; A 21 is Arg or Val; A 22 is Asp, Glu, Lys or Orn; A 25 is Arg or His; A 26 is His or Lys; A 29 is Ala or Gln; and A 30 is Asp or Glu; and the side chains of A 18 and A 22 are linked through an amide bond to form a bridge.
10 . A peptide compound according to claim 5 , or a pharmaceutically acceptable salt or prodrug thereof wherein A 10 is Asn or Asp; A 13 is Lys; A 14 is His or Ser; A 17 is Asp or Ser; A 18 is Nle; A 21 is Asp or Lys; A 22 is Glu or Phe; A 25 is Asp or Lys; A 26 is His or Lys; A 29 is Ala or Gln; and A 30 is Asp or Glu; and the side chains of A 25 and A 29 are linked through an amide bond to form a bridge.
11 . A peptide compound according to claim 5 , or a pharmaceutically acceptable salt or prodrug thereof wherein A 10 is Asn or Asp; A 13 is Lys; A 14 is His or Ser; A 17 is Asp or Ser; A 18 is Nle; A 21 is Arg or Val; A 22 is Glu or Phe; A 25 is Asp or Lys; A 26 is His or Lys; A 29 is Asp or Lys; and A 30 is Asp or Glu; and the side chains of A 25 and A 29 are linked through an amide bond to form a bridge.
12 . A peptide compound according to claim 4 , or a pharmaceutically acceptable salt or prodrug thereof wherein
(i) the side-chains of A 13 and A 17 are linked through an amide bond and the side-chains of A 18 and A 22 are linked through an amide bond to form a bridge; and (ii) the side-chains of A 18 and A 22 are linked through an amide bond and the side-chains of A 26 and A 30 are linked through an amide bond to form a bridge.
13 . A peptide compound according to claim 12 , or a pharmaceutically acceptable salt or prodrug thereof wherein A 10 is Asn or Asp; A 13 is Lys or Asp; A 14 is His or Ser; A 17 is Lys or Asp; A 18 is Lys or Asp; A 21 is Val or Arg; A 22 is Glu, Lys or Asp; A 25 is Arg or His; A 26 is His or Lys; A 29 is Ala or Gln; and A 30 is Asp or Glu; and the side-chains of A 13 and A 17 are linked through an amide bond and the side-chains of A 18 and A 2 are linked through an amide bond to form a bridge.
14 . A peptide compound according to claim 12 , or a pharmaceutically acceptable salt or prodrug thereof wherein A 10 is Asn or Asp; A 13 is Lys; A 14 is His or Ser; A 17 is Ser or Asp; A 18 is Lys or Asp; A 21 is Val or Arg; A 22 is Glu, Lys or Asp; A 25 is Arg or His; A 26 is Lys or Asp; A 29 is Ala or Gln; and A 30 is Lys or Asp; and the side-chains of A 18 and A 22 are linked through an amide bond and the side-chains of A 26 and A 30 are linked through an amide bond to form a bridge.
15 . A peptide compound according to claim 4 , or a pharmaceutically acceptable salt or prodrug thereof wherein the side-chains of A 13 and A 17 are linked through an amide bond and the side-chains of A 18 and A 22 are linked through an amide bond and the side chains of A 26 and A 30 are linked through an amide bond to form a bridge.
16 . A peptide compound according to claim 15 , or a pharmaceutically acceptable salt or prodrug thereof, wherein A 10 is Asn or Asp; A 13 is Lys or Asp; A 14 is His or Ser; A 17 is Lys or Asp; A 18 is Lys or Asp; A 21 is Val or Arg; A 22 is Glu, Lys or Asp, A 25 is Arg or His; A 26 is Lys or Asp; A 29 is Ala or Gln; and A 30 is Lys or Asp.
17 . Bicyclo(K 13 -D 17 ,K 26 -D 30 )[A 1 ,Nle 8,18 ,D 17 ,L 27 ]hPTH(1-31)NH 2 (SEQ ID NO: 79) or a pharmaceutically acceptable salt or prodrug thereof.
18 . A peptide compound according to claim 2 , or a pharmaceutically acceptable salt or prodrug thereof wherein
X is selected from the group consisting of
(a) R 1a -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -,
(b) R 1a -A 5 -A 6 -A 7 -A 8 -A 9 -,
(c) R 1a -A 6 -A 7 -A 8 -A 9 -,
(d) R 1a -A 7 -A 8 -A 9 ,
(e) R 1a -A 8 -A 9 ,
(f) R 1b -A 9 -, and
(g) R 1b -;
19 . A peptide compound according to claim 18 , or a pharmaceutically acceptable salt or prodrug thereof wherein A 8 is Nle and A 27 is Leu.
20 . A peptide compound according to claim 19 , or a pharmaceutically acceptable salt or prodrug thereof wherein the side chains of A 18 and A 22 are linked through an amide bond to form a bridge.
21 . A peptide compound according to claim 20 , or a pharmaceutically acceptable salt or prodrug thereof wherein A 10 is Asn or Asp; A 13 is Lys; A 14 is His or Ser; A 17 is Asp or Ser; A 18 is Asp, Lys or Orn; A 21 is Arg or Val; A 22 is Asp, Glu, Lys or Orn; A 25 is Arg or His; A 26 is His or Lys; A 29 is Ala or Gln; and A 30 is Asp or Glu.
22 . A peptide compound according to claim 1 selected from
cyclo(K 18 -D 22 )[K 18 ,D 22 ,L 27 ]hPTH(10-31)NH 2 (SEQ ID NO: 56);
cyclo(K 18 -D 22 )[K 18 ,D 22 ,L 27 ]hPTH(9-31)NH 2 (SEQ ID NO: 57);
cyclo(K 18 -D 22 )[Nle 8 ,K 18 ,D 22 ,L 27 ]hPTH(8-31)NH 2 (SEQ ID NO: 58);
cyclo(K 18 -D 22 )[Nle 8 ,K 18 ,D 22 ,L 27 ]hPTH(7-31)NH 2 (SEQ ID NO: 59);
cyclo(K 18 -D 22 )[Nle 8 ,K 18 ,D 22 ,L 27 ]hPTH(6-31)NH 2 (SEQ ID NO: 60);
cyclo(K 18 -D 22 )[Nle 8 ,K 18 ,D 22 ,L 27 ]hPTH(5-31)NH 2 (SEQ ID NO: 61);
cyclo(K 18 -D 22 )[Nle 8 ,K 18 ,D 22 ,L 27 ]hPTH(5-31)NH 2 (SEQ ID NO: 62);
cyclo(K 18 -D 22 )[Nle 8 ,K 18 ,D 22 ,L 27 ]hPTH(4-34)NH 2 (SEQ ID NO: 65); and
cyclo(K 18 -D 22 )[K 18 ,D 22 ]hPTHrP(7-34)NH 2 (SEQ ID NO: 77);
or a pharmaceutically acceptable salt or prodrug thereof.
23 . A method of treating diseases associated with calcium regulation in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a peptide compound of claim 3 , or a pharmaceutically acceptable salt or prodrug thereof.
24 . The method of claim 23 wherein said diseases associated with calcium regulation in the body are selected from hypocalcemia; osteopaenia, osteoporosis; hyperparathyroidism; hypoparathyroidism; glucocorticoid- and immunosuppresant-induced osteopaenia; and bone fracture and refracture.
25 . A method of treating osteopaenia or osteoporosis in a host mammal in need of such treatment comprising administering to a mammal in need of such treatment a therapeutically effective amount of a peptide compound of claim 3 , or a pharmaceutically acceptable salt or prodrug thereof.
26 . The method of claim 23 comprising the pulsatile subcutaneous or intrapulmonary administration of a therapeutically effective amount of a peptide compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof.
27 . The method of claim 25 comprising the pulsatile subcutaneous or intrapulmonary administration of a therapeutically effective amount of a peptide compound of claim 2 , or a pharmaceutically acceptable salt or prodrug thereof.
28 . A method of treating diseases associated with calcium regulation in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a peptide compound of claim 18 , or a pharmaceutically acceptable salt or prodrug thereof.
29 . The method of claim 28 wherein said diseases associated with calcium regulation in the body are selected from hyperparathyrodism and hyperparathyrodism-related hypercalcemia crisis, hypercalcemia of malignancy, renal failure and hypertension.
30 . The method of claim 28 - comprising the pulsatile subcutaneous or intrapulmonary administration of a therapeutically effective amount of a peptide compound of claim 18 , or a pharmaceutically acceptable salt or prodrug thereof.
31 . The method of claim 29 comprising the pulsatile subcutaneous or intrapulmonary administration of a therapeutically effective amount of a peptide compound of claim 18 , or a pharmaceutically acceptable salt or prodrug thereof.
32 . A peptide compound of formula
X-A 10 -A 11 -A 12 -A 13 -A 14 -A 15 -A 16 -A 17 -A 18 -A 19 -A 20 -A 21 -A 22 -A 23 -A 24 -A 25 -A 26 -A 27 -Y
or a pharmaceutically acceptable salt or prodrug thereof wherein
X is selected from the group consisting of
(a) R 1a -A 0 -A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -,
(b) R 1a -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -,
(c) R 1b -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -,
(d) R 1a -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -,
(e) R 1a -A 5 -A 6 -A 7 -A 8 -A 9 -,
(f) R 1a -A 6 -A 7 -A 8 -A 9 -,
(g) R 1a -A 7 -A 8 -A 9 -,
(h) R 1a -A 8 -A 9 -, and
(i) R 1a -A 9 -, and
(j) R 1a -;
Y is selected from the group consisting of
(a ) -R 3 ,
(b) -A 28 -R 3 ,
(c) -A 28 -A 29 -R 3 ,
(d) -A 28 -A 29 -A 30 -R 3 ,
(e) -A 28 -A 29 -A 30 -A 31 -R 3 ,
(f) -A 28 -A 29 -A 30 -A 31 -A 32 -R 3 ,
(g) -A 28 -A 29 -A 30 -A 31 -A 32 -A 33 -R 3 , and
(h) -A 28 -A 29 -A 30 -A 31 -A 32 -A 33 -A 34 -R 3 ;
R 1a is H, alkyl, aralkyl or —COR 2 ;
R 1b is R 1a or a group of formula
R 2 is alkyl, alkenyl, alkynyl, aryl or aralkyl;
R 3 is a group of formula A 35 -OR 4 or A 35 -NR 4 R 5 ;
R 4 and R 5 are independently H or lower alkyl;
R 6 and R 9 are independently H or alkyl;
R 7 is alkyl;
R 8 is H, alkyl or COR 2 ;
R 10 is H or halogen;
R 11 is alkyl or aralkyl;
A 0 is absent or a peptide of from one to six amino acid residues;
A 1 is Ser, Ala, Gly or D-Pro or an equivalent amino acid thereof;
A 2 is Ala, Val, Gly or an equivalent amino acid thereof;
A 3 is Ala, Ser, Gly or D-Pro or an equivalent amino acid thereof;
A 4 is Glu, Ala or Gly or an equivalent amino acid thereof;
A 5 is Ile, His, Ala or Gly or an equivalent amino acid thereof;
A 6 is Ala, Gln, Gly or D-Pro or an equivalent amino acid thereof;
A 7 is Ala, Leu, Gly or an equivalent amino acid thereof;
A 8 is Leu, Nle or Gly or D-Pro or an equivalent amino acid thereof;
A 9 is His, Ala, Gly or D-Pro or an equivalent amino acid thereof;
A 10 is Ala, Asn, Gly Lys, Asp or D-Pro or an equivalent amino acid thereof;
A 11 is Ala, Gly, Leu or Lys or an equivalent amino acid thereof;
A 12 is Ala or Gly or an equivalent amino acid thereof;
A 13 is Ala, Gly or Lys or an equivalent amino acid thereof;
A 14 is Ala, Gly, His, Ser, Asp, Lys or D-Pro or an equivalent amino acid thereof;
A 15 is Ala, Gly, Ile, D-Pro or Leu or an equivalent amino acid thereof;
A 16 is Asn, Ala, Gly, D-Pro or Gln or an equivalent amino acid thereof;
A 17 is Ala, Asp, Gly, Ser, Lys or D-Pro or an equivalent amino acid thereof;
A 18 is Lys or an equivalent amino acid thereof;
A 19 is Arg or Glu or an equivalent amino acid thereof;
A 20 is Arg or an equivalent amino acid thereof;
A 21 is Arg, Lys, Asp or Val or an equivalent amino acid thereof;
A 22 is Asp, Lys, Orn -or Glu or an equivalent amino acid thereof;
A 23 is Leu, Phe or Trp or an equivalent amino acid thereof;
A 24 is Leu or an equivalent amino acid thereof;
A 25 is Arg, His, Asp, Lys or Gin or an equivalent amino acid thereof;
A 26 is Lys or His or an equivalent amino acid thereof;
A 27 is Leu or Lys or an equivalent amino acid thereof;
A 28 is Ile or Leu or an equivalent amino acid thereof;
A 29 is Ala, Asp, Glu or Gln or an equivalent amino acid thereof;
A 30 is Asp, Lys or Glu or an equivalent amino acid thereof;
A 31 is Ile, Leu or Val or an equivalent amino acid thereof;
A 32 is His or an equivalent amino acid thereof;
A 33 is Asn or Thr or an equivalent amino acid thereof; and
A 34 is Ala or Phe or an equivalent amino acid thereof; and
A 35 is absent or a peptide of from 1 to 4 amino acids.
33 . A peptide compound according to claim 32 , or a pharmaceutically acceptable salt or prodrug thereof wherein R 1a is H and Y is NH 2 .
34 . A peptide compound according to claim 33 , or a pharmaceutically acceptable salt or prodrug thereof wherein X is
(a) R 1a -A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -, (b) R 1a -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 - or (c) R 1a -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -.
35 . A peptide compound according to claim 34 , or a pharmaceutically acceptable salt or prodrug thereof wherein
A 1 is Ser, Ala, Gly or D-Pro; A 2 is Ala, Val or Gly; A 3 is Ala, Ser, Gly or D-Pro; A 4 is Glu, Ala or Gly; A 5 is Ile, His, Ala or Gly; A 6 is Ala, Gln, Gly or D-Pro; A 7 is Ala, Leu, Gly; A 8 is Leu, Nle, Gly or D-Pro; A 9 is His, Ala, Gly or D-Pro; A 10 is Ala, Asn, Gly, Asp or D-Pro; A 11 is Ala, Gly, Leu or Lys; A 12 is Ala or Gly; A 13 is Ala, Gly or Lys; A 14 is Ala, Gly, His, Ser or D-Pro; A 15 is Ala, Gly, Ile or D-Pro; A 16 is Asn, Ala, Gly, D-Pro or Gln; A 17 is Ala, Asp, Gly, Ser or D-Pro; A 18 is Lys; A 19 is Arg or Glu; A 20 is Arg; A 21 is Arg or Val; A 22 is Asp, Lys, Orn or Glu; A 23 is Leu, Phe or Trp; A 24 is Leu; A 25 is Arg or His; A 26 is Lys or His; A 27 is Leu or Lys; A 28 is Ile or Leu or an equivalent amino acid thereof; A 29 is Ala or Gln; A 30 is Asp or Glu; A 31 is Ile, Leu or Val; A 32 is His; A 33 is Asn or Thr; and A 34 is Ala or Phe.
36 . A peptide compound according to claim 35 , or a pharmaceutically acceptable salt or prodrug thereof wherein A 1 is Ala, Gly or D-Pro; A 8 is Nle, A 22 is Asp and A 27 is Leu.
37 . A peptide compound according to claim 36 , or a pharmaceutically acceptable salt or prodrug thereof wherein X is R 1a -A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -.
38 . A peptide compound according to claim 1 which is
[A 1 ,Nle 8 ,K 18 ,D 22 ,L 27 ]hPTH(1-31)NH 2 (SEQ ID NO: 4)
or a pharmaceutically acceptable salt or prodrug thereof.
39 . A pharmaceutical composition comprising a peptide compound of claim 32 , or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier.
40 . A method of treating diseases associated with calcium regulation in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a peptide compound of claim 32 , or a pharmaceutically acceptable salt or prodrug thereof.
41 . The method of claim 40 wherein said diseases associated with calcium regulation in the body are selected from hypocalcemia; osteopaenia, osteoporosis; hyperparathyroidism; hypoparathyroidism; glucocorticoid- and immunosuppresant-induced osteopaenia; and bone fracture and refracture.
42 . A method of treating osteopaenia or osteoporosis in a host mammal in need of such treatment comprising administering to a mammal in need of such treatment a therapeutically effective amount of a peptide compound of claim 32 , or a pharmaceutically acceptable salt or prodrug thereof.
43 . The method of claim 40 comprising the pulsatile subcutaneous or intrapulmonary administration of a therapeutically effective amount of a peptide compound of claim 33 , or a pharmaceutically acceptable salt or prodrug thereof.
44 . The method of claim 42 comprising the pulsatile subcutaneous or intrapulmonary administration of a therapeutically effective amount of a peptide compound of claim 33 , or a pharmaceutically acceptable salt or prodrug thereof.
45 . A peptide compound according to claim 1 which is
Cyclo(K 18 -D 22 )[A 1 ,Nle 8 ,K 18 ,D 22 ,L 27 ]hPTH(1-34)NH 2 (SEQ ID NO: 46)
or a pharmaceutically acceptable salt or prodrug thereof.
46 . A peptide compound according to claim 1 which is
Cyclo(K 18 -D 22 )[A 1,10 ,Nle 8 ,K 18 ,D 22 ,L 27 ]hPTH(1-31)NH 2 (SEQ ID NO: 12)
or a pharmaceutically acceptable salt or prodrug thereof.
47 . A peptide compound according to claim 1 which is
Cyclo(K 18 -D 22 )[A 1,12 ,Nle 8 ,K 18 ,D 22 ,L 27 ]hPTH(1-31)NH 2 (SEQ ID NO: 14)
or a pharmaceutically acceptable salt or prodrug thereof.
48 . A peptide compound according to claim 1 which is
Cyclo(K 18 -D 22 )[A 1,13 ,Nle 8 ,K 18 ,D 22 ,L 27 ]hPTH(1-31)NH 2 (SEQ ID NO: 15)
or a pharmaceutically acceptable salt or prodrug thereof.
49 . A peptide compound according to claim 1 which is
Cyclo(K 18 -D 22 )[A 1,14 ,Nle 8 ,K 18 ,D 22 ,L 27 ]hPTH(1-31)NH 2 (SEQ ID NO; 16)
or a pharmaceutically acceptable salt or prodrug thereof.
50 . A peptide compound according to claim 1 which is
Cyclo(K 18 -D 22 )[A 1,16 ,Nle 8 ,K 18 ,D 22 ,L 27 ]hPTH(1-31)NH 2 (SEQ ID NO: 18)
or a pharmaceutically acceptable salt or prodrug thereof.
51 . A peptide compound according to claim 1 which is
Cyclo(K 18 -D 22 )[A 1,17 ,Nle 8 ,K 18 ,D 22 ,L 27 ]hPTH(1-31)NH 2 (SEQ ID NO: 19)
or a pharmaceutically acceptable salt or prodrug thereof.
52 . A peptide compound according to claim 1 which is
Cyclo(K 18 -D 22 )[A 1 ,G 3 ,Nle 8 ,K 18 ,D 22 ,L 27 ]hPTH(1-31)NH 2 (SEQ ID NO: 22)
or a pharmaceutically acceptable salt or prodrug thereof.
53 . A peptide compound according to claim 1 which is
Cyclo(K 18 -D 22 )[A 1 ,G 13 ,Nle 8 ,K 18 ,D 22 ,L 27 ]hPTH(1-31)NH 2 (SEQ ID NO: 31)
or a pharmaceutically acceptable salt or prodrug thereof.
54 . A peptide compound according to claim 1 which is
Cyclo(K 18 -D 22 )[A 1 ,G 16 ,Nle 8 ,K 18 ,D 22 ,L 27 ]hPTH(1-31)NH 2 (SEQ ID NO: 34)
or a pharmaceutically acceptable salt or prodrug thereof.
55 . A peptide compound according to claim 1 which is
Cyclo(K 18 -D 22 )[A 1 ,G 17 ,Nle 8 ,K 18 ,D 22 ,L 27 ]hPTH(1-31)NH 2 (SEQ ID NO: 35)
or a pharmaceutically acceptable salt or prodrug thereof.
56 . A peptide compound according to claim 1 which is
Cyclo(K 18 -D 22 )[D-P 1 ,Nle 8 ,K 18 ,D 22 ,L 27 ]hPTH(1-31)NH 2 (SEQ ID NO: 36)
or a pharmaceutically acceptable salt or prodrug thereof.
57 . A peptide compound according to claim 1 which is
Cyclo(D 18 -K 22 )[A 1 ,Nle 8 ,D 18 ,K 22 ,L 27 ]hPTH(1-31)NH 2 (SEQ ID NO: 47)
or a pharmaceutically acceptable salt or prodrug thereof.
58 . A peptide compound according to claim 1 which is
Cyclo(K 18 -E 22 )[A 1 ,Nle 8 ,K 18 ,E 22 ,L 27 ]hPTH(1-31)NH 2 (SEQ ID NO: 50)
or a pharmaceutically acceptable salt or prodrug thereof.
59 . A peptide compound according to claim 1 which is
Cyclo(O 18 -E 22 )[A 1 ,Nle 8 ,O 18 ,E 22 ,L 27 ]hPTH(1-31)NH 2 (SEQ ID NO: 51)
or a pharmaceutically acceptable salt or prodrug thereof.
60 . A peptide compound according to claim 1 which is
Cyclo(K 18 -D 22 )[A 1 ,Nle 8 ,K 18 ,D 22 ,L 27 ]hPTH(1-30)NH 2 (SEQ ID NO: 52)
or a pharmaceutically acceptable salt or prodrug thereof.
61 . A peptide compound according to claim 1 which is
Cyclo(K 14 -D 8 )[A 1 ,Nle 8 ,K 14 ,D 18 ,L 27 ]hPTH(1-31)NH 2 (SEQ ID NO: 67)
or a pharmaceutically acceptable salt or prodrug thereof.
62 . A peptide compound according to claim 1 which is
Cyclo(K 18 -D 22 )[K 18 ,D 22 ]hPTHrP(1-34)NH 2 (SEQ ID NO: 71)
or a pharmaceutically acceptable salt or prodrug thereof.
63 . A peptide compound according to claim 1 which is
Bicyclo(K 13 -D 17 ,K 18 -D 22 )[A 1 ,Nle 8 ,D 17,22 ,K 18 ,L 27 ]hPTH(1-31)NH 2 (SEQ ID NO: 73)
or a pharmaceutically acceptable salt or prodrug thereof.
64 . A peptide compound according to claim 1 which is
Bicyclo(K 18 -D 22 ,K 26 -D 30 )[A 1 ,Nle 8 ,K 18 ,D 22 ,L 27 ]hPTH(1-3 l)NH 2 (SEQ ID NO: 74)
or a pharmaceutically acceptable salt or prodrug thereof.
65 . A peptide compound according to claim 1 which is
Tricyclo(K 13 -D 17 ,K 18 -D 22 ,K 26 -D 30 )[A 1 ,Nle 8 ,K 18 ,D 17,22 ,L 27 ]hPTH(1-31)NH 2 (SEQ ID NO: 80)
or a pharmaceutically acceptable salt or prodrug thereof.Join the waitlist — get patent alerts
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