Heterobifunctional inhibitors of E-selectin and galectin-3
Inventors
Magnani, John L. • Peterson, John M. • Sarkar, Arun K. • VOHRA, Yusufbhai U. • Ghosh, Indranath • NOGUEIRA, Jason
Assignees
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Publication Number
US-11845771-B2
Publication Date
2023-12-19
Expiration Date
Abstract
Compounds, compositions, and methods for treatment and/or prevention of at least one disease, disorder, and/or condition by inhibiting binding of an E-selectin, galectin-3, or E-selectin and galectin-3 to ligands are disclosed. For example, heterobifunctional inhibitors of E-selectin and galectin-3 are described and pharmaceutical compositions comprising at least one such agent is described.
Core Innovation
The invention relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, including heterobifunctional agents having an E-selectin-binding module linked to a galectin-3-binding module. The compound structures are defined by substituents R1 through R9 and a linker L, with group M, X, and Q selected within stated structural constraints. The compounds include variable substituents chosen from defined structural classes and bounded selection rules.
The document describes heterobifunctional inhibitors that block E-selectin and galectin-3 binding to ligands. It addresses the biological roles of E-selectin and galectin-3, including leukocyte/endothelial adhesion processes mediated by sLeX/sLea, tumor cell binding, inflammation, fibrosis, tumor growth, and metastasis. The compounds are also described with prodrugs and subject administration concepts.
The provided partial content also describes preparation of prophetic glycosylated conjugate compounds by changing aromatic, alkynyl, and benzyl substituents and by downstream functional-group interconversions. It includes an example coupling between compound 14 and a prepared compound 50 to yield compound 51, followed by generation of compounds 52–72 from compound 50 using the same coupling approach.
Claims Coverage
The claim coverage centers on a Formula (I) compound family with extensive structural variability across substituents R1–R9 and a linker L. Four inventive features are identifiable across the provided claim summaries.
Formula (I) heterobifunctional compounds with an E-selectin-binding module and a galectin-3-binding module linked via linker L
At least one compound chosen from compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein the compound structure is defined with substituents R1–R9 and a linker L, and wherein group M is defined with X and Q, with each of these groups selected according to the stated options and constraints.
Extensive substituent selection for R1–R5
R1 is selected from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, and C2-8 haloalkynyl groups; R2 is selected from —OH, —OY1, halo, —NH2, —NY1Y2, —OC(=O)Y1, —NHC(=O)Y1, and —NHC(=O)NHY1; R3 is selected from —CN, —CH2CN, and —C(=O)Y3; R4 is selected from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, C2-8 haloalkynyl, C4-16 cycloalkylalkyl, and C6-18 aryl; and R5 is selected from —CN, C1-8 alkyl, and C1-4 haloalkyl.
M-associated scaffold definition using X and Q options with R8/R9 selection
M is chosen from the defined scaffold where X is chosen from O, S, CH2, or N(R10) with R10 options; Q is chosen from H, halo, and –OZ3 groups with Z3 = H and C1-8 alkyl; R8 is chosen from H and multiple substituted hydrocarbon and aryl/heteroaryl/arylalkyl/heteroarylalkyl classes optionally substituted with halo, C1-8 hydroxyalkyl, C1-8 haloalkyl, aryl, and additional group options; and R9 is chosen from aryl and heteroaryl groups optionally substituted with R11 and further substituent options.
Linker L selection for Formula (I) compounds
L is chosen from linker groups, providing the linker attachment framework for the Formula (I) compounds.
The independent claim is centered on Formula (I) compounds and pharmaceutically acceptable salts defined by broad substituent-selection rules across R1–R9, an M-associated scaffold with defined X and Q options, and a linker L.
Stated Advantages
Blocks E-selectin binding to ligands.
Blocks galectin-3 binding to ligands.
Targets diseases described in the document, including inflammatory conditions, fibrosis, thrombosis, atherosclerosis/cardiovascular disease, cancer adhesion/metastasis, mucositis, pathological angiogenesis, neurological disorders, and mobilization of hematopoietic cells.
Documented Applications
Treatment and/or prevention of inflammatory diseases, fibrosis, and cancer by administering pharmaceutical compositions containing Formula (I) compounds to a subject.
Inflammation.
Fibrosis.
Thrombosis.
Atherosclerosis/cardiovascular disease.
Cancer adhesion/metastasis, including bone marrow-related processes.
Mucositis.
Pathological angiogenesis.
Neurological disorders.
Mobilization of hematopoietic cells, including hematopoietic stem cells and bone marrow infiltrating lymphocytes.
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