Molecular degraders of extracellular proteins
AssigneeYale University
InventorsDavid Caianiello, Edward DeRamon, David Spiegel
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Abstract
The disclosure describes compounds of Formula Ia, which in non-limiting aspects contain an asialoglycoprotein receptor (ASGPR) binding moiety and an anti-β1AR binding moiety. Compounds of Formula Ia are useful in preventing, treating, and/or ameliorating heart failure in a subject when administered in therapeutically effective amounts.
Claims14
A compound of Formula Ia, or a pharmaceutically acceptable salt thereof, having the structure:
- wherein:
- is a carbon-carbon single or double bond;
- A is C6-18 aryl, C6-18 heterocyclyl, C6-18 biaryl, or C6-18 heterobiaryl, wherein each of C6-18 aryl, C6-18 heterocyclyl, C6-18 biaryl, and C6-18 heterobiaryl is independently optionally substituted by 1-6 substituents selected from the group consisting of F, Cl, Br, I, O(RG), OC(O)N(RG)2, CN, NO, NO2, ONO2, CF3, OCF3, (RG), N(RG)2, S(RG), SO(RG), SO2(RG), SO2N(RG)2, and SO3(RG);
- LA is an asialoglycoprotein receptor (ASGPR) binding moiety with the structure
- LB is an anti-β1AR binding moiety with the structure
- AA is an amino acid sequence at least 80% homologous to SEQ ID NO:1;
- each occurrence of RG1′ is independently
- each occurrence of RG1 is independently H or
- each occurrence of ZG is:
- AG is
- RG2 is H;
- RG3 is C(═O)CH3;
- each occurrence of RG is independently H, unsubstituted or substituted C1-10 alkyl, unsubstituted or substituted C3-10 cycloalkyl, unsubstituted or substituted C6-18 aryl, or unsubstituted or substituted C5-18 heteroaryl;
- each occurrence of XG is independently selected from the group consisting of one or more of —CH2—, —C(═O)—, —NH—, and —O—;
- m is 2, 3, 4, 5, 6, 7, 8, 9, or 10;
- n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;
- and
- p is 1, 2, 3, or 4.
A method of ameliorating heart failure in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula Ia
- wherein:
- is a carbon-carbon single or double bond;
- A is C6-18 aryl, C6-18 heterocyclyl, C6-18 biaryl, or C6-18 heterobiaryl, wherein each of C6-18 aryl, C6-18 heterocyclyl, C6-18 biaryl, and C6-18 heterobiaryl is independently optionally substituted by 1-6 substituents selected from the group consisting of F, Cl, Br, I, O(RG), OC(O)N(RG)2, CN, NO, NO2, ONO2, CF3, OCF3, (RG), N(RG)2, S(RG), SO(RG), SO2(RG), SO2N(RG)2, and SO3(RG);
- LA is an asialoglycoprotein receptor (ASGPR) binding moiety with the structure
- LB is an anti-β1AR binding moiety with the structure
- AA is an amino acid sequence at least 80% homologous to SEQ ID NO:1;
- each occurrence of RG1′ is independently
- each occurrence of RG1 is independently H or
- each occurrence of ZG is:
- AG is
- RG2 is H;
- RG3 is C(═O)CH3;
- each occurrence of RG is independently H, unsubstituted or substituted C1-10 alkyl, unsubstituted or substituted C3-10 cycloalkyl, unsubstituted or substituted C6-18 aryl, or unsubstituted or substituted C5-18 heteroaryl;
- each occurrence of XG is independently selected from the group consisting of one or more of —CH2—, —C(═O)—, —NH—, and —O—;
- m is 2, 3, 4, 5, 6, 7, 8, 9, or 10;
- n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;
- and
- p is 1, 2, 3, or 4.
Dependencies are inferred from the claim text.