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US-20260125410-A1 - MOLECULAR DEGRADERS OF EXTRACELLULAR PROTEINS

US20260125410A1US 20260125410 A1US20260125410 A1US 20260125410A1US-20260125410-A1

Abstract

The disclosure describes compounds of Formula Ia, which in non-limiting aspects contain an asialoglycoprotein receptor (ASGPR) binding moiety and an anti-β 1 AR 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.

Inventors

  • David Caianiello
  • Edward DERAMON
  • David Spiegel

Assignees

  • YALE UNIVERSITY

Dates

Publication Date
20260507
Application Date
20250213

Claims (12)

  1. 1 . A compound of Formula I, or a pharmaceutically acceptable salt thereof, having the structure: wherein: is a connecting linker between L A and L B with the structure wherein L A and L B are covalently bonded to either of the open valences in shown by the wavy lines; L A is an asialoglycoprotein receptor (ASGPR) binding moiety with the structure L B is an anti-β 1 AR binding moiety with the structure AA is an amino acid sequence at least 80% homologous to SEQ ID NO: 1; each occurrence of RG 1′ is independently each occurrence of RG 1 is independently H or each occurrence of ZG is: AG is RG 2 is H; RG 3 is C(═O)CH 3 ; each occurrence of XG is independently selected from the group consisting of one or more of —CH 2 —, —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.
  2. 2 . The compound of claim 1 , wherein Formula I has the structure:
  3. 3 . The compound of claim 1 , wherein Formula I has the structure:
  4. 4 . The compound of claim 1 , wherein AA is a (6,12) cyclic peptide in which the cysteine residues at positions 6 and 12 in AA form a disulfide bond.
  5. 5 . The compound of claim 1 , wherein AA is at least 95% homologous to SEQ ID NO:1.
  6. 6 . The compound of claim 1 , wherein AA is an amino acid sequence of SEQ ID NO: 1.
  7. 7 . A composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  8. 8 . A composition comprising the compound of claim 2 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  9. 9 . A composition comprising the compound of claim 3 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  10. 10 . A composition comprising the compound of claim 4 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  11. 11 . A composition comprising the compound of claim 5 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  12. 12 . A composition comprising the compound of claim 6 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

Description

CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation of, and claims priority to, U.S. application Ser. No. 18/180,634 filed Mar. 8, 2023, now allowed, which is a continuation of, and claims priority to, PCT International Application No. PCT/US2022/075527, filed Aug. 26, 2022, which claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63/237,627, filed Aug. 27, 2021, the disclosure of each of which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with government support under GM067543 awarded by National Institutes of Health. The government has certain rights in this invention. INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED AS A TEXT FILE This disclosure contains one or more sequences in a computer readable format in an accompanying text file titled “047162-7328WO1_ST26.xml,” which is 120,878 bytes in size and was generated Aug. 26, 2022, the contents of which are incorporated herein by reference in their entirety. BACKGROUND Pathogenic anti-β1ECII (the second extracellular loop of the β1 adrenergic receptor) autoantibodies have been shown to cause dilated cardiomyopathy (DCM) and other forms of heart failure. Existing literature has suggested that neutralization or removal of these antibodies can alleviate disease. Existing treatments for DCM, such as β1-AR (adrenoreceptor) blockers and whole IgG depletion, are associated with significant undesirable side effects such as fatigue and dizziness, poor circulation, gastrointestinal symptoms, and sexual dysfunction. Accordingly, there is an ongoing need for more selective and rapidly active treatment of DCM. The present disclosure fulfills this need. BRIEF SUMMARY In various aspects, a compound of Formula Ia, or a pharmaceutically acceptable salt thereof is provided. wherein: is a carbon-carbon single or double bond;A is a C6-18 aryl, C6-18 heterocyclyl, C6-18 biaryl, or C6-18 heterobiaryl, each of which is optionally substituted by 1-6 substituents selected from the group consisting of F, Cl, Br, I, ORG, OC(O)N(RG)2, CN, NO, NO2, ONO2, CF3, OCF3, RG, N(RG)2, SRG, SORG, SO2RG, SO2N(RG)2, and SO3RG;LA is an 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;RG1′ is each occurrence of R1 is independently hydrogen or AG is an aminosaccharide;each occurrence of RG is independently H, optionally substituted C1-10 alkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C6-18 aryl, or optionally substituted C5-18 heteroaryl;each occurrence of XG is independently selected from the group consisting of —CH2—, —C(═O)—, —NH—, and —O—;each occurrence of ZG is independently selected from the group consisting of —CH2—, —C(═O)—, —NH—, and —O—;m is an integer from 2 to 10;n is an integer from 1 to 100; andp is an integer from 1 to 50. In various aspects, the compounds of the disclosure are useful in method of preventing, treating, and/or ameliorating heart failure in a subject when administered in therapeutically effective amounts. BRIEF DESCRIPTION OF THE FIGURES The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present application. FIG. 1 is a schematic illustration of one mode of action of compounds of Formula I, in accordance with various embodiments. Without wishing to be bound by theory, the mode of action of the compounds here is at least in part as follows: Step 1: MoDE-A binds target protein of interest; Step 2: MoDE-A/protein complex binds ASGPR on hepatocyte; Step 3: ASGPR/MoDE-A/protein ternary complex is endocytosed into hepatocyte; Step 4: Ternary complex dissociates; Step 5: Endocytosed target protein is degraded; and Step 6: ASGPR and MoDE-A are recycled back outside of the cell. FIGS. 2A-2B show data demonstrating in vitro endocytosis of target antibodies. FIG. 2A shows flow cytometry data showing the successful endocytosis of the target antibody (aβ1AR) in the presence of varying concentrations compounds of Formula I. FIG. 2B shows inhibition of endocytosis by binding ASGPR or aβ1AR (anti-β1AR) target antibodies. FIGS. 3A-3B show data demonstrating ternary complex formation with target antibodies. FIG. 3A shows flow cytometry data indicating formation of a ternary complex between hepatocytes, compounds of Formula I, and aβ1AR target antibodies. FIG. 3B shows the fold-change in the concentration of aβ1AR target antibodies as a function of the dose of compounds of Formula I. FIG. 4 shows in vivo depletion of target aβ1AR antibodies in the presence of a compound of Formula I as compared to a control compound (COR1-OH3). PBS=phosphate buffered saline; mpk=mg/kg. FIG. 5 shows the chemical structure of α-DNP (dinitrophenyl) antibody binding control molecule. FIGS. 6A-6C show ternary complex formation. FIG. 6A shows formation of a ternary complex between