Prevention of pancreatic cell degeneration
Inventors
Reaume, Andrew G. • Saporito, Michael S. • Ochman, Alexander R.
Assignees
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Publication Number
US-12011445-B2
Publication Date
2024-06-18
Expiration Date
Abstract
The present invention relates to compounds and pharmaceutically acceptable salts thereof and formulations comprising the compounds or a pharmaceutically acceptable salts thereof that are useful in methods of preventing pancreatic beta cell degeneration or methods of treating a disorder associated with pancreatic beta cell degeneration, such as type I diabetes.
Core Innovation
The disclosure provides uracil/pyrimidinedione-type compounds defined by structural formulas, including compounds of Formulas I-XI and related formula sets such as Formula (VIII) and Formula (VIIIa), with further named variants such as Formula (VIIIb), Formula (IX), Formula (X), and Formula (XI). The compounds are characterized by variable substituents and parameters including alkyl groups, halogens, integers n and m, and additional substituent positions such as R1-R8 and R9-R11, together with Z1/Z2, L1, and protecting groups R100/R200.
The document describes a therapeutic and prophylactic strategy for preventing pancreatic beta cell degeneration and for treating type I diabetes (IDDM/juvenile diabetes) in a mammal, including a human subject, by administering an effective amount of a composition that contains a compound of the disclosed formula and pharmaceutically acceptable salts and/or prodrugs thereof. The approach is directed to increasing insulin content and preserving pancreatic islet structure in pancreatic islets.
The problem addressed is pancreatic beta cell degeneration associated with type I diabetes, including loss of serum insulin and pancreatic beta cell degeneration. In the provided preclinical context, dosing of Compound 102 is associated with decreased blood glucose and prevention of serum insulin loss and pancreatic beta cell degeneration, together with preservation of islet structure and changes in insulin-related readouts.
Claims Coverage
The independent claims cover a treatment method for pancreatic beta cell degeneration in a human, with three independent claim sets that share the core inventive concept of increasing insulin content and preserving islet structure, and that differ mainly in the specific compound formula constraints and the oral composition/dosage framing.
Treating pancreatic beta cell degeneration by increasing insulin content and preserving islet structure
A method of treating pancreatic beta cell degeneration by increasing insulin content and preserving islet structure in pancreatic islets in a human in need thereof comprising administering to the human in need thereof an effective amount of a composition comprising a compound of formula wherein R1 is an alkyl group; X is a halogen; n is an integer from 0 to 5; and m is 0 or 1; wherein m+n is less than or equal to 5.
Treating pancreatic beta cell degeneration by increasing insulin content and preserving islet structure with simplified formula constraints
A method of treating pancreatic beta cell degeneration by increasing insulin content and preserving islet structure in pancreatic islets in a human in need thereof comprising administering to the human in need thereof an effective amount of a composition comprising a compound of formula wherein R1 is an alkyl group and n is an integer from 0 to 5.
Treating pancreatic beta cell degeneration using an oral composition with a specified dosage range
A method of treating pancreatic beta cell degeneration by increasing insulin content and preserving islet structure in pancreatic islets in a human in need thereof comprising administering to the human in need thereof an effective amount of an oral composition comprising 0.5 mg to 20 mg per kg body weight of a compound of formula.
Across the independent claims, coverage centers on administering an effective amount of a composition containing a disclosed formula compound to a human to increase insulin content and preserve islet structure during pancreatic beta cell degeneration. The claims narrow the chemical scope via formula parameters and additionally frame at least one embodiment as an oral composition with a specified dosage range.
Stated Advantages
Preventing pancreatic beta cell degeneration.
Treating disorders such as type I diabetes.
Increasing insulin content.
Preserving islet structure in pancreatic islets.
Prevention of serum insulin loss.
Decreased blood glucose.
Therapeutic treatment of pancreatic beta cell degeneration in a human.
Prophylactic prevention of pancreatic beta cell degeneration.
Documented Applications
Therapeutic treatment and prophylactic prevention of pancreatic beta cell degeneration in type I diabetes (IDDM/juvenile diabetes), including in a human subject.
Preclinical context in db/db mice showing decreased blood glucose and prevention of serum insulin loss and pancreatic beta cell degeneration upon dosing Compound 102.
Assessment of insulin-related and structural outcomes in vivo using readouts including glucose reduction and islet structure preservation assessed by histology and insulin staining.
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