PTHR1 RECEPTOR COMPOUNDS

• US 20110294738A1
• Filed: 11/04/2009
• Published: 12/01/2011
• Est. Priority Date: 11/04/2008
• Status: Abandoned Application

• Current Assignee: Athan Kuliopulos, Thomas J. Mcmurry, Yong Ren
• Original Assignee: Athan Kuliopulos, Thomas J. Mcmurry, Yong Ren
• Inventors: Ren, Yong, Kuliopulos, Athan, McMurry, Thomas J.
• Application Number:
  US13/127,694
• Publication Number:
  US 20110294738A1
• Time in Patent Office: Days
• US Class Current: 514/16.9
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C07K 14/72 for hormones for neuromediators C07K14/70571

Abstract

The invention relates generally to compounds which are allosteric modulators (e.g., negative and positive allosteric modulators, allosteric agonists, and ago-allosteric modulators) of the G protein coupled receptor PTHR1, also known as parathyroid hormone/parathyroid hormone related protein receptor. The PTHR1 compounds are derived from the intracellular loops and domains of the PTHR1 receptor. The invention also relates to the use of these PTHR1 receptor compounds and pharmaceutical compositions comprising the PTHR1 receptor compounds in the treatment of diseases and conditions associated with PTHR1 receptor modulation, such as osteoporosis; humoral hypercalcemia of malignancy; osteolytic and osteoblastic metastasis to bone; primary and secondary hyperparathyroidism associated increase in bone absorption; vascular calcification; psychiatric disorders and cognitive disorders associated with hyperparathyroidism; dermatological disorders; and excess hair growth.

Claims

1. A compound selected from the following group:

9. The compound of claim 1, wherein P is selected from SEQ ID NOS:

101-111.

18. A method of treating diseases and conditions associated with PTHR1 modulation in a patient in need thereof comprising administering to said patient and effective amount of a compound of claim 1.

19. The method of claim 18, wherein the disease or condition is selected from:

osteoporosis;

humoral hypercalcemia of malignancy;

osteolytic and osteoblastic metastasis to bone;

primary and secondary hyperparathyroidism associated increase in bone absorption;

vascular calcification;

psychiatric disorders and cognitive disorders associated with hyperparathyroidism;

dermatological disorders; and

excess hair growth.

20. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

2. A compound selected from the following group:

3. A compound selected from the following group:

4. A compound selected from the following group:

5. A compound represented by Formula I:

T-L-P,

or pharmaceutically acceptable salts thereof, wherein;

P is a peptide sequence selected from;

SEQ ID NOS;

2-33;

SEQ ID NOS;

35-44;

SEQ ID NOS;

46-99; and

SEQ ID NOS;

101-111;

L is a linking moiety represented by C(O) and bonded to P at an N terminal nitrogen of an N-terminal amino-acid residue;

and T is a lipophilic tether moiety bonded to L, where the C-terminal amino acid residue of P is optionally functionalized.

6. The compound of claim 5, wherein P is selected from SEQ ID NOS:

2-33.

7. The compound of claim 5, wherein P is selected from SEQ ID NOS:

35-44.

8. The compound of claim 5, wherein P is selected from SEQ ID NOS:

46-99.

10. The compound of claim 5, wherein T is an optionally substituted (C₆-C₃₀)alkyl, (C₆-C₃₀)alkenyl, (C₆-C₃₀)alkynyl, wherein 0-3 carbon atoms are replaced with oxygen, sulfur, nitrogen or a combination thereof.

11. The compound of claim 10, wherein T is selected from the group consisting of:

CH₃(CH₂)₁₆, CH₃(CH₂)₁₅, CH₃(CH₂)₁₄, CH₃(CH₂)₁₃, CH₃(CH₂)₁₂, CH₃(CH₂)₁₁, CH₃(CH₂)₁₀, CH₃(CH₂)₉, CH₃(CH₂)₈, CH₃(CH₂)₉OPh-, CH₃(CH₂)₆C═

C(CH₂)₆, CH₃(CH₂)₁₁O(CH₂)₃, and CH₃(CH₂)₉O(CH₂)₂.

12. The compound of claim 5, wherein T is a fatty acid derivative.

13. The compound of claim 12, wherein the fatty acid is selected from the group consisting of:

butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, α

-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid.

14. The compound of claim 5, wherein T is a bile acid derivative.

15. The compound of claim 14, wherein the bile acid is selected from the group consisting of:

lithocholic acid, chenodeoxycholic acid, deoxycholic acid, cholanic acid, cholic acid, ursocholic acid, ursodeoxycholic acid, isoursodeoxycholic acid, lagodeoxycholic acid, dehydrocholic acid, hyocholic acid, and hyodeoxycholic acid.

16. The compound of claim 5, wherein T is selected from sterols;

progestagens;

glucocorticoids;

mineralcorticoids; and

rogens; and

estrogens.

17. The compound of claim 5, wherein TL is selected from:

CH₃(CH₂)₁₅—

C(O);

CH₃(CH₂)₁₃—

C(O);

CH₃(CH₂)₉O(CH₂)₂C(O);

CH₃(CH₂)₁₀O(CH₂)₂C(O);

CH₃(CH₂)₆C═

C(CH₂)₆—

C(O);

LCA-C(O); and

CH₃(CH₂)₉OPh-C(O) wherein