Inhibitors of neutral endopeptidase/CALLA as chemotherapeutic agents

• US 5,200,426 A
• Filed: 08/14/1990
• Issued: 04/06/1993
• Est. Priority Date: 08/14/1990
• Status: Expired due to Fees

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Hersh, Louis B., Bateman, R. C. Jr.
• Primary Examiner(s): Rotman, Alan L.
• Assistant Examiner(s): OWENS, AMELIA A
• Application Number:
  US07/567,499
• Time in Patent Office: 966 Days
• Field of Search: 562/444, 562/448, 562/564, 562/567, 562/576, 549/551, 514/475, 514/564, 514/565, 514/563
• US Class Current: 514/475
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 38/55 Protease inhibitors
• CPC Class Codes: C07C 235/78 the carbon skeleton containing rings
• CPC Class Codes: C07C 245/18 the carbon skeleton being further substituted by carboxyl groups
• CPC Class Codes: C07C 255/21 the carbon skeleton being further substituted by doubly-bound oxygen atoms
• CPC Class Codes: C07C 255/40 the carbon skeleton being further substituted by doubly-bound oxygen atoms
• CPC Class Codes: C07C 259/06 having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07D 303/46 by amide or nitrile radicals
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N

Abstract

The present disclosure relates to inhibitors of neutral endopeptidase (NEP) which are proposed as novel agents for the treatment of CALLA+ positive cancers as well as other conditions such as hypertension.

Claims

1. A method of inhibiting the growth or differentiation of CALLA+ human leukemia cells comprising subjecting such cells to an effective amount of an NEP inhibitor.

2. The method of claim 1, wherein the NEP inhibitor is an irreversible inhibitor.

3. The method of claim 1, wherein the NEP inhibitor is an affinity-label inhibitor.

4. The method of claim 3, wherein the affinity label inhibitor comprises BADLG, or a derivative thereof, wherein alanine or beta-alanine is substituted for glycine.

5. The method of claim 4, wherein the NEP inhibitor comprises BADLG wherein a hydrophobic amino acid is substituted for D-Leu.

6. The method of claim 5, wherein the hydrophobic amino acid comprises D-Val or D-Ile.

7. The method of claim 5, wherein the hydrophobic amino acid is rendered inactive by modification to the alpha-nitrogen.

8. The method of claim 7, wherein the hydrophobic amino acid comprises bromoacetyl-(N-methyl) (Leu or Phe)-Ala, or bromoacetyl-(N-hydroxy)(Leu or Phe)-Ala.

9. The method of claim 1, wherein the NEP inhibitor comprises an NEP inhibitor with the formula:

##STR19## wherein;

X=--CH₂ --φ

, isopropyl or isobutyl,

or a derivative or analog thereof.

10. The method of claim 9, wherein the NEP inhibitor comprises a substitution for the BrCH₂ group.

11. The method of claim 1, wherein the NEP inhibitor comprises an inactivated N-acyl substrate analog.

12. The method of claim 11, wherein the inactivated N-acyl substrate has the formula:

##STR20##

13. The method of claim 11, wherein the inactivated N-acyl substrate contains a chelating ligand.

14. The method of claim 13, wherein the inactivated N-acyl substrate is:

##STR21##

15. The method of claim 1, wherein the NEP inhibitor comprises an acetylene or nitrile substrate analog.

16. The method of claim 15, wherein the NEP inhibitor has the formula:

##STR22## wherein;

S1=benzyl, isobutyl, or their analogs; and

S2 =Ala, β

-Ala, gly or their analogs.

17. The method of claim 16, wherein the NEP inhibitor has the formula:

##STR23##

18. The method of claim 1, wherein the NEP inhibitor comprises a diazoketone-containing substrate analog.

19. The method of claim 18, wherein the NEP inhibitor has the chemical formula:

##STR24## wherein;

S1=benzyl, isobutyl, or their analogs; and

S2=Ala, β

-Ala, gly or their analogs.

20. The method of claim 18 wherein the NEP inhibitor has the formula:

##STR25##

21. The method of claim 18 wherein the NEP inhibitor has the formula:

##STR26##

22. The method of claim 1, wherein the inhibitor compound is:

##STR27##

23. An NEP inhibitor comprising BADLG, or a derivative thereof, wherein alanine or beta-alanine is substituted for glycine.

24. The NEP inhibitor of claim 23, wherein a hydrophobic amino acid is substituted for the D-Leu of BADLG.

25. The NEP inhibitor of claim 24, wherein the hydrophobic amino acid comprises D-Val or D-Ile.

26. The NEP inhibitor of claim 24, wherein the hydrophobic amino acid is rendered inactive by modification to the alpha-nitrogen.

27. The NEP inhibitor of claim 26, wherein the hydrophobic amino acid comprises bromoacetyl-(N-methyl) (Leu or Phe)-Ala, or bromoacetyl-(N-hyroxy)(Leu or Phe)-Ala.

28. An NEP inhibitor which comprises the formula:

##STR28## wherein;

X=--CH₂ --φ

, isopropyl or isobutyl,

or a derivative or analog thereof.

29. An NEP inhibitor having the formula:

##STR29##

30. An NEP inhibitor having the formula:

##STR30## wherein;

S1=benzyl, isobutyl, or their analogs; and

S2=Ala, β

-Ala, gly or their analogs.

31. The NEP inhibitor of claim 30, wherein the NEP inhibitor has the formula:

##STR31##

32. An NEP inhibitor having the formula:

##STR32## wherein;

S1=benzyl, isobutyl, or their analogs; and

S2=Ala, β

-Ala, gly or their analogs.

33. The NEP inhibitor of claim 32 wherein the NEP inhibitor has the formula:

##STR33##

34. The method of claim 32 wherein the NEP inhibitor has the formula:

##STR34##

35. An NEP inhibitor having the formula:

##STR35##