SPHINGAMIDE COMPOUNDS AND METHODS FOR BINDING iNKT CELLS

Patent metadata

Field	Value
Publication number	US-2019256541-A1
Application number	US-201615775770-A
Country	US
Kind code	A1
Filing date	Nov 14, 2016
Priority date	Nov 13, 2015
Publication date	Aug 22, 2019
Grant date	—

Abstract

The compounds, compositions and methods provided herein antagonize, inhibit, decrease, reduce, suppress, or disrupt CD1d-mediated, iNKT cell-mediated, and/or iNKT cell TCR-mediated immune signaling. The sphingamide compounds were rationally designed based upon 3D structural considerations in relation to the structures of each of CD1d, the iNKT cell TCR, and the ternary complex CD1d-a-GalCer analog lipids-TCR. More specifically, the addition of an amide in the phytosphingosine tail of a derivative of α-GalCer led to a non-conserved binding with CD1d, a conserved binding with the iNKT cell TCR, and an antagonist-like phenotype.

First claim

1 . A compound comprising formula I, a pharmaceutically acceptable salt thereof, or a prodrug thereof:

wherein X represents an alkyl chain having 3 to 30 carbons and having:
i. at least one intervening amide group and terminating in a phenyl group; or
ii. a terminating alkyl substituted anilide;

wherein Y is an alkyl chain having 5 to 30 carbons;
wherein Z represents OH;
wherein L represents an oxygen atom or a C-glycoside analogue thereof.

2 . The compound according to claim 1 having the structure of formula II, a pharmaceutically acceptable salt thereof, or a prodrug thereof:

wherein X′ is:
i. an alkyl chain having two to 8 carbons terminating in a phenyl group; or
ii. an alkyl substituted phenyl group.

3 . A compound according to claim 2 , wherein X′ is selected from the group consisting of:

4 . A compound according to claim 1 , wherein Y is selected from the group consisting of:
a C 27 H 55 unbranched alkyl chain; a C 25 H 51 unbranched alkyl chain; a C 23 H 47 unbranched alkyl chain; and a C 7 H 15 unbranched alkyl chain.

5 . (canceled)

6 . The compound of claim 1 , wherein the compound binds one or more of CD1 or an NKT cell TCR.

7 . The compound according to claim 6 , wherein the CD1 is CD1d and the NKT cell TCR is an iNKT cell TCR.

8 . (canceled)

9 . The compound according to claim 7 , wherein the CD1d is a human CD1d sequence having the amino acid sequence of SEQ ID NO: 4 or a sequence having substantial identity thereto.

10 - 11 . (canceled)

12 . The compound according to claim 7 wherein the compound binds CD1d in a non-conserved manner when compared to the binding of α-GalCer.

13 . The compound according to claim 7 , wherein the compound binds an iNKT cell TCR in a conserved manner when compared to the binding of α-GalCer.

14 - 16 . (canceled)

17 . The compound according to claim 7 , wherein the binding affinity to CD1d or the iNKT cell TCR is in the nanomolar range.

18 . A composition comprising the compound of claim 1 and one or more additional active ingredients and/or one or more inactive ingredients.

19 . The composition according to claim 18 , wherein the active ingredient is a spacer lipid.

20 . (canceled)

21 . A method of treating an immunomodulatory disease comprising administering the composition of claim 1 to a patient in need thereof.

22 . The method of claim 21 , wherein the immunomodulatory disease is selected from the group consisting of multiple sclerosis, experimental autoimmune encephalomyelitis (both relapsing and remitting), rheumatoid arthritis, anaphylactic hypersensitivity, asthma, allergic rhinitis, atopic dermatitis, vernal conjunctivitis, eczema, urticarial, food allergies, allergic encephalomyelitis, multiple sclerosis, insulin-dependent diabetes mellitus, and autoimmune uveoretinitis, inflammatory bowel disease, Crohn's disease, regional enteritis, distal ileitis, granulomatous enteritis, regional ileitis, terminal ileitis, ulcerative colitis, autoimmune thyroid disease, hypertension, infectious diseases, Leishmania major, Mycobacterium leprae, Candida albicans, Toxoplasma gondi , respiratory syncytial virus, human immunodeficiency virus, allograft rejection, graft vs host disease, airway hyper reactivity, atherosclerosis, inflammatory liver disease, and cancer.

23 . The method according to claim 22 , wherein the immunomodulatory disease is selected from allograft rejection (such as graft vs host disease), airway hyper reactivity, atherosclerosis, inflammatory liver disease, and cancer.

24 . (canceled)

25 . The method according to claim 24 , wherein the administration is topical, by inhalation, intranasal, intravenous, intra-articular, intra-arterial, intraperitoneal, intra-thecal, intraventricular, intrasternal, intracranial, intra-muscular or subcutaneous, or by infusion techniques.

26 . A method of antagonizing, inhibiting, decreasing, reducing, suppressing, or disrupting CD1d-mediated, iNKT cell-mediated, and/or iNKT cell TCR-mediated immune signaling comprising administering a composition comprising the compound according to claim 1 to a subject.

27 . The method according to claim 26 , wherein the immune signaling is triggered by a self-antigen.

28 . The method according to claim 26 , wherein the CD1d-mediated, iNKT cell-mediated, and/or iNKT cell TCR-mediated immune signaling is the production or inhibition of production of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), IL-1, IL-2, IL-3, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-16, IL-18 and IL-23, MIP-1a, MIP-113, RANTES, CCL4, CCL5, or GMCSF.

29 . The method according to claim 28 , wherein the CD1d-mediated, iNKT cell-mediated, and/or iNKT cell TCR-mediated immune signaling is the production or inhibition of production of interferon-gamma (IFN-γ), IL-4, or GMCSF.

30 - 32 . (canceled)

Assignees

• La Jolla Inst For Allergey And Immunology
• Univ Of Gent
• Vib Vzw
• La Jolla Inst Allergy & Immunology
• Univ Gent

Inventors

• Zajonc Dirk
• Van Calenbergh Serge
• Elewaut Dirk
• Guillaume Joren

Classifications

• A61P31/12

  Antivirals · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07H15/18 Primary

  Acyclic radicals, substituted by carbocyclic rings · CPC title

• C07H15/04 Primary

  attached to an oxygen atom of the saccharide radical · CPC title