Method for inhibiting osteoclast development
Inventors
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Assignees
University of Pittsburgh • Temple University
MemberWest Virginia UniversityWest Virginia UniversityWest Virginia University is a public R1 research institution offering diverse undergraduate and graduate programs across science, engineering, business, creative arts, and media. The university emphasizes experiential learning, research, and innovation, with notable strengths in academic program development, research excellence, community engagement, and a commitment to affordability, career readiness, and student success. WVU supports a vibrant campus environment, industry partnerships, and impactful scholarship, preparing students for careers through hands-on education, research, and applied learning.
West Virginia University is a public R1 research institution offering diverse undergraduate and graduate programs across science, engineering, business, creative arts, and media. The university emphasizes experiential learning, research, and innovation, with notable strengths in academic program development, research excellence, community engagement, and a commitment to affordability, career readiness, and student success. WVU supports a vibrant campus environment, industry partnerships, and impactful scholarship, preparing students for careers through hands-on education, research, and applied learning.
Publication Number
US-11654123-B2
Publication Date
2023-05-23
Expiration Date
Abstract
This invention provides a composition comprising Formula I, or salt thereof, wherein X is chlorine, Y is a methyl group, and R is an alkyl group having a carbon chain length of three carbon atoms. A method of inhibiting osteoclast development and a method for preventing bone erosion in a patient using the compositions of Formula I are disclosed.
Core Innovation
The disclosed invention concerns haloanilide compositions of Formula I, including embodiments where X is chlorine or bromine, Y is hydrogen or a C1–C5 alkyl group, and R is a C1–C5 alkyl group, while excluding N-(3,4-dichlorophenyl)propanamide (DCPA). The compositions are described as selective inhibitors of store-operated Ca2+ entry (CRAC/STIM1–Orai1 Ca2+ entry) mediated by STIM1–Orai1 signaling. The disclosure links CRAC inhibition to inhibition of osteoclast development, including osteoclast differentiation outcomes relevant to bone erosion and inflammation.
The described problem is that osteoclast development and bone erosion are associated with arthritis, and that CRAC/STIM1–Orai1 Ca2+ entry activity is required for osteoclast fusion and osteoclast differentiation. The disclosure further states that DCPA inhibits CRAC through disruption of STIM1–Orai1 and that osteoclast fusion requires CRAC activity. Accordingly, the invention addresses CRAC/STIM1–Orai1 inhibition as a means to reduce osteoclast development and bone erosion in the context of arthritis.
The disclosure reports that osteoclast differentiation driven by RANKL is associated with time-dependent decreases in STIM1/2 and Orai1 expression/function, while pharmacologic CRAC inhibition and Orai1 knockdown reduce the formation of multinucleated osteoclasts. It also states that TRAP induction is not reduced under these CRAC inhibition conditions. The disclosure further reports that selected haloanilides suppress STIM1 puncta formation and attenuate STIM1ct translocation triggered by 2-APB, while describing the resulting osteoclast-related outcomes as tied to CRAC inhibition.
Claims Coverage
The partial content provides two independent claims. Across these claims, the inventive coverage centers on administering a specific Formula I haloanilide (or salt) with defined substituent constraints and excluding N-(3,4-dichlorophenyl)propanamide, for inhibition of osteoclast development and prevention of bone erosion in arthritis.
Haloanilide composition of Formula I for inhibiting osteoclast development
A method of inhibiting osteoclast development comprising administering an effective amount of a haloanilide composition or a salt thereof to an osteoclast cell, where the haloanilide composition is not N-(3,4-dichlorophenyl)propanamide, and where the haloanilide is a composition of Formula I with X being chlorine, Y being a methyl group, and R being an alkyl group having a carbon chain length of three carbon atoms.
Haloanilide composition of Formula I for preventing bone erosion in arthritis
A method for preventing bone erosion in a patient diagnosed with arthritis comprising administering to a patient an effective amount of a haloanilide composition or salt thereof for preventing bone erosion, where the haloanilide composition is not N-(3,4-dichlorophenyl)propanamide, and where the haloanilide is a composition of Formula I with X being chlorine, Y being a methyl group, and R being an alkyl group having a carbon chain length of three carbon atoms.
Both independent claims require administration of a Formula I haloanilide (or salt) with X=chlorine, Y=methyl, and R as a three-carbon alkyl, while excluding N-(3,4-dichlorophenyl)propanamide, for osteoclast development inhibition or for preventing bone erosion in arthritis.
Stated Advantages
Selective inhibition of CRAC/STIM1–Orai1 Ca2+ entry.
Reduction of multinucleated osteoclast formation without reducing TRAP induction.
Suppression of STIM1 puncta formation and attenuation of STIM1ct translocation triggered by 2-APB.
Selected Formula I haloanilides are described as having a lower toxicity burden than DCPA.
Documented Applications
Inhibiting osteoclast development by administering a Formula I haloanilide composition (excluding N-(3,4-dichlorophenyl)propanamide).
Preventing bone erosion in a patient diagnosed with arthritis by administering a Formula I haloanilide composition (excluding N-(3,4-dichlorophenyl)propanamide).
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