Bis-octahydrophenanthrene carboxamides and protein conjugates thereof
Provided herein are compounds, compositions and methods for the treatment of diseases and disorders associated with the liver X receptor, including bis-octahydrophenanthrene carboxamides and protein (e.g., antibody) drug conjugates thereof.
1. A compound of Formula A
or a pharmaceutically acceptable salt, or stereoisomeric form thereof, wherein
L is a linker or X—Y—Z, wherein
X is —NH— or —O—;
Y is an enzymatically cleavable moiety; a self-immolative group; an acid-labile moiety comprising an alkoxamine, ketoxamine, carbonate, or phosphonate; PEG n ; a sugar moiety comprising a glucuronide; and/or an enhancement group comprising a cyclodextrin and/or an alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid; and
Z is a binding agent linker (BL) wherein Z is covalently bound to BA;
BA is an antibody or antigen binding fragment thereof;
k ranges from about one to about eight, representing an average number of units of a payload conjugated to BA;
each of Q 1 and Q 2 is independently —CH 2 , C(O)—, —C(H)(OH)—, or —C(OH) 2 —;
W is —CH 2 —, —N(H)—, or —O—;
R is independently hydrogen, —OH, C 1-6 alkyl, or —OP (O)(OR 6 )(OH); and
each R 6 is, independently in each instance, hydrogen, an amino acid residue, a peptide, or alkyl; and
each R 7 is independently halo, C 1-6 alkyl, C 1-6 alkoxy, —CN, O-glucose, O-amino acid residue, or O-PEG n , wherein each n is an integer from zero to three.
2. The compound of claim 1 , comprising BA linked via a linker L to a compound selected from the group consisting of
or a regioisomer, stereoisomeric form, pharmaceutically acceptable salt, or solvate thereof; wherein k ranges from about one to about four, representing an average number of units of a payload conjugated to BA.
3. The compound of claim 1 , comprising BA linked to a compound selected from the group consisting of
or a regioisomer, stereoisomeric form, pharmaceutically acceptable salt, or solvate thereof; wherein k ranges from about one to about four, representing an average number of units of a payload conjugated to BA.
4. The compound of claim 1 , selected from the group consisting of
or a regioisomer, stereoisomeric form, pharmaceutically acceptable salt, or solvate thereof; wherein k ranges from about one to about four, representing an average number of units of a payload conjugated to BA.
5. The compound of claim 4 , wherein k is about two.
6. The compound of claim 4 , wherein k is about four.
7. The compound of claim 4 , wherein BA is an antibody or antigen binding fragment thereof having binding specificity for an antigen selected from the group consisting of class A-J scavenger receptors.
8. The compound of claim 4 , wherein BA is an antibody or antigen binding fragment thereof having binding specificity for an antigen selected from the group consisting of MSR1, MARCO, SRCL, SCARA5, COLEC12, CD36, LIMPII, SRBI, SRBII, CD68, LAMP, LOX-1, Dectin-1, SREC-I, SREC-II, MEGF, CXCL16, Fasciclin, FEEL-1, FEEL-2, CD163, RAGE, C-type lectin superfamily members, DEC205, CD206, Dectin-2, Mincle, DC-SIGN, DNGR-1, VSIG4, CSFIR, ASGPR, and APLP-2.
9. The compound of claim 4 , wherein BA is an antibody or antigen binding fragment thereof having binding specificity for Her2 or PRLR.
10. The compound of claim 4 , wherein BA is an antibody or antigen binding fragment thereof having binding specificity for MSR1.
11. The compound of claim 4 , wherein BA is an antibody or antigen binding fragment thereof linked through one or more N295 residues.
12. The compound of claim 4 , wherein BA is an antibody or antigen binding fragment thereof linked through one or more N295 and N297Q residues.
13. The compound of claim 1 , having the structure
wherein BA is a binding agent; and k ranges from about one to about four, representing an average number of units of a payload conjugated to BA.
14. The compound of claim 1 , having the structure
wherein BA is a binding agent; and k ranges from about one to about eight, representing an average number of units of a payload conjugated to BA.
15. The compound of claim 1 , having the structure
wherein BA is a binding agent; and k ranges from about one to about eight, representing an average number of units of a payload conjugated to BA.
16. The compound of claim 1 , having the structure
wherein BA is a binding agent; and k ranges from about one to about eight, representing an average number of units of a payload conjugated to BA.
17. The compound of claim 1 , selected from the group consisting of
or a regioisomer, stereoisomeric form, pharmaceutically acceptable salt, or solvate thereof, wherein k ranges from about one to about four, representing an average number of units of a payload conjugated to BA.
18. The compound of claim 1 , comprising BA linked via a linker to a compound as depicted in the following formula
19. The compound of claim 3 , wherein BA is an antibody or antigen binding fragment thereof conjugated to a primary amine compound at a glutamine residue, and L is bonded to BA through the primary amine compound.
20. The compound of claim 19 , wherein the primary amine compound comprises a divalent PEG group.
21. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient, carrier, or diluent.
22. A method for the treatment of dyslipidemia in a subject comprising the administration to the subject an effective treatment amount of the compound of claim 1 .
23. A method for the treatment of dyslipidemia in a subject comprising the administration to the subject an effective treatment amount of the pharmaceutical composition of claim 21 .