Inhibitors of protein arginine deiminases (pads) and methods of preparation and use thereof

Patent metadata

Field	Value
Publication number	US-2020339518-A1
Application number	US-201716464317-A
Country	US
Kind code	A1
Filing date	Nov 27, 2017
Priority date	Dec 2, 2016
Publication date	Oct 29, 2020
Grant date	—

Abstract

The invention provides novel inhibitors or inactivators of protein arginine deiminases, pharmaceutical compositions and methods of use thereof. The invention also relates to molecular probes based on such compounds and methods of use thereof.

First claim

1 . A compound having the structural formula (I),

wherein
each of R a and R b is independently selected from the group consisting of H, D and F;
L is a bivalent hydrocarbyl linker, optionally with one or more carbon atoms replaced by a heteroatom selected from the group consisting of O, S and N;
X is a halogen atom;
Y is N, O or S; provided that when Y is S or O, its bonding to the adjacent carbons are single bonds;
Z is N—R 1 , O or S;
R 1 is selected from the group consisting of: H, a C 1-6 alkyl, OH, a C 1-3 alkoxy, CF 3 , COCH 3 , or COCF 3 groups;
each of R 2 , R 3 , R 4 and R 5 is independently selected from the group consisting of: H, hydroxyl, halogen atom, C 1-6 alkyl, C 1-6 alkoxy, alkynyl, CF 2 Re c , or OCF 2 R, groups, where Re is H, F or alkyl; and
R 6 is a group comprising a cyclic alkyl or aryl moiety,

or a pharmaceutically acceptable form thereof.

2 . The compound of claim 1 , wherein each of R a and R b is H.

3 . The compound of claim 1 , wherein L is a —(CH 2 ) n —, wherein n is an integer from 1 to about 4.

4 . (canceled)

5 . The compound of claim 1 , wherein Y is N and Z is N—R 1 with the compound having the structural formula (II):

6 . (canceled)

7 . (canceled)

8 . The compound of claim 1 , wherein R 1 is a C 1-6 alkyl group or H.

9 . (canceled)

10 . The compound of claim 1 , wherein each of R 2 , R 3 , R 4 and R 5 is H.

11 . The compound of claim 1 , wherein at least one of R 2 , R 3 , R 4 and R 5 is a group selected from the group consisting of hydroxyl, F, Cl, C 1-6 alkyl, C 1-6 alkoxy, alkynyl, CF 2 R c , and OCF 2 R, groups, where Re is H, F or alkyl.

12 . The compound of claim 11 , wherein one of R 2 and R 3 is a group selected from the group consisting of hydroxyl, F, Cl, C 1-6 alkyl, C 1-6 alkoxy, alkynyl, CF 2 R c , and OCF 2 R, groups, where R c is H, F or alkyl.

13 - 16 . (canceled)

17 . The compound of claim 1 , wherein R 6 is selected from the group consisting of:

wherein
R 7 is independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, halogen atoms, aryl, —COOR 8 , ethynyl, alkynyl, CF 2 R c , and OCF 2 R c , where R c is H, F or alkyl;
R 8 is independently selected from the group consisting of H and C 1-6 alkyl; and
R 9 is CH 2 , O, NH or S.

18 . The compound of claim 17 , wherein R 7 is H.

19 . The compound of claim 17 , wherein R 8 is a C 1-6 alkyl group.

20 . A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient, carrier, or diluent.

21 - 26 . (canceled)

27 . A unit dosage form comprising a pharmaceutical composition according to claim 1 .

28 . A method for treating, reducing, or preventing a disease or disorder, comprising administering to a subject in need thereof an effective amount of-a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient, carrier, or diluent, wherein the diseases or disorder is selected from the group consisting of immune system diseases or disorders, inflammatory diseases or disorders, and cancer or related diseases or disorders.

29 - 33 . (canceled)

34 . A method for inhibiting or inactivating a protein arginine deiminase, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient, carrier, or diluent, effective to inhibit or inactivate a biological function of a protein arginine deiminase, in a mammal, including a human.

35 . The method of claim 34 , wherein the protein arginine deiminase is selected from the group consisting of: PAD1, PAD2, PAD3 and PAD4.

36 . (canceled)

37 . (canceled)

38 . A molecular imaging probe having the structural formula:
A F -L F -W   (II)
wherein
A F is a group comprising an optically detectable moiety;
L F is a linking group; and
W is group comprising a benzimidazole moiety, or a derivative or analog thereof, capable of inhibiting or inactivating a biological function of a protein arginine deiminase.

39 . The molecular imaging probe of claim 38 , wherein A F is a group comprising a fluorophore selected from the group consisting of xanthene dyes, cyanine dyes, coumarin dyes and bodipy dyes and the protein arginine deiminase is selected from the group consisting of: PAD1, PAD2, PAD3 and PAD4.

40 - 47 . (canceled)

48 . The molecular imaging probe of claim 38 , wherein W is a monovalent radical derived from a compound having the structural formula:

wherein,
each of R a and R b is independently selected from the group consisting of H, D and F;
L is a bivalent hydrocarbyl linker, optionally with one or more carbon atoms replaced by a heteroatom selected from the group consisting of O, S and N;
X is a halogen atom;
Y is N, O or S; provided that when Y is S or O, its bonding to the adjacent carbons are single bonds;
Z is N—R 1 , O or S;
R 1 is selected from the group consisting of: H, a C 1-6 alkyl, OH, a C 1-3 alkoxy, CF 3 , COCH 3 , and COCF 3 groups;
each of R 2 , R 3 , R 4 and R 5 is independently selected from the group consisting of: H, hydroxyl, halogen atom, C 1-6 alkyl, C 1-6 alkoxy, alkynyl, CF 2 R c and OCF 2 R c groups, where R c is H, F or alkyl; and

R 6 is a group comprising a cyclic alkyl or aryl moiety.

49 . A method for identifying a protein arginine deiminase inhibitor or inactivator, comprising:
performing a competitive assay wherein a test compound competes with a molecular imaging probe according to claim 38 to bind to a protein arginine deiminase; and measuring fluorescence to determine an amount of fluorescent protein arginine deiminase present in the test assay.

50 - 52 . (canceled)

Assignees

• Univ Massachusetts

Inventors

• Thompson Paul R
• Muth Aaron
• Subramanian Venkataraman

Classifications

• C12Q1/34

  involving hydrolase · CPC title

• C12Y305/03015

  Protein-arginine deiminase (3.5.3.15) · CPC title

• G01N2333/978

  acting on carbon to nitrogen bonds other than peptide bonds (3.5) · CPC title

• C12Q1/25

  involving enzymes not classifiable in groups C12Q1/26 {- C12Q1/66} · CPC title

• G01N33/582

  with fluorescent label · CPC title