Sphingamide compounds and methods for binding iNKT cells

Patent metadata

Field	Value
Publication number	US-10723750-B2
Application number	US-201615775770-A
Country	US
Kind code	B2
Filing date	Nov 14, 2016
Priority date	Nov 13, 2015
Publication date	Jul 28, 2020
Grant date	Jul 28, 2020

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

What is claimed:

1. A compound of formula I, or a pharmaceutically acceptable salt 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, or a pharmaceutically acceptable salt 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. The compound according to claim 2 , wherein X′ is selected from the group consisting of:

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

6. The compound according to claim 5 , wherein the CD1 is CD1d and the NKT cell TCR is an iNKT cell TCR.

7. The compound according to claim 6 , wherein the CD1d id a human CD1d sequence having the amino acid sequence of SEQ ID NO: 4 or a sequence having substantial identity thereto.

8. The compound according to claim 6 wherein the compound binds CD1d in a non-conserved manner when compared to the binding of α-GalCer.

9. The compound according to claim 6 , wherein the compound binds an iNKT cell TCR in a conserved manner when compared to the binding of α-GalCer.

10. The compound according to claim 6 , wherein the binding affinity to CD1d or the iNKT cell TCR is in the nanomolar range.

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

12. The composition according to claim 11 , wherein the active ingredient is a spacer lipid.

13. The compound according to claim 1 , having the structure of:

wherein R═C 25 H 51 .

14. The compound according to claim 1 , having the structure of:

wherein R═C 19 H 39 .

15. The compound according to claim 1 , having the structure of:

wherein R═C 15 H 31 .

16. The compound according to claim 1 , having the structure of:

wherein R═C 11 H 23 .

Assignees

• La Jolla Inst Allergy & Immunology
• Univ Gent
• Vib Vzw

Inventors

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

Classifications

• C07H15/06

  being a hydroxyalkyl group esterified by a fatty acid · CPC title

• C07H15/18 Primary

  Acyclic radicals, substituted by carbocyclic rings · CPC title

• A61P31/12

  Antivirals · CPC title

• A61K31/7028

  Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages · CPC title

• A61P37/04

  Immunostimulants · CPC title