Nonpeptide somatostatin type 5 receptor agonists and uses thereof
Inventors
Zhao, Jian • ZHU, Yunfei • Wang, Shimiao • Chen, Mi • Pontillo, Joseph
Assignees
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Publication Number
US-11479540-B2
Publication Date
2022-10-25
Expiration Date
Abstract
Described herein are compounds that are somatostatin modulators, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of somatostatin activity.
Core Innovation
The disclosure defines substituted pyridine-3-carboxamide compounds selected from enumerated structures, including stereochemical variants and pharmaceutically acceptable salt or solvate forms. The compounds share a pyridine-3-carboxamide scaffold bearing a chiral aminopyrrolidinyl substituent or related amino-containing ring motif, together with varied aryl, heteroaryl, fluorinated, cyclic, and bridged-ring substituents.
The disclosed compound sets include fluoro, methoxy, bromo, cyano, difluoromethoxy, trifluoromethyl, trifluoropropyl, and difluorinated variants, as well as ring systems such as cyclopropyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentan-1-yl, and adamantan-2-yl. Selected compounds are identified as explicit numbered examples within the enumerated set, with stereochemical designations such as (3S), (3R), and (2S).
The patent further provides broad Formula (I) definitions in which Ring A is a carbocycle or heterocycle and X, Y, and Z are independently N or C—R, with variable substituent classes defined for R groups, linkers, and fused-ring options. The selected compounds and Formula (I) framework are linked to pharmaceutical composition claims and methods for treating hyperinsulinemia in a mammal by administration of the selected compounds.
Claims Coverage
The consolidated claim coverage includes one broad Formula (I) compound claim and compound-selection claims directed to enumerated substituted pyridine-3-carboxamide structures. Across the combined claim set, the inventive features center on the broad variable-defined scaffold and the selected stereodefined pyridine-3-carboxamide compounds, with optional pharmaceutically acceptable salt or solvate forms.
Formula (I) compound scaffold definition
A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is carbocycle or heterocycle; X, Y, and Z are each independently N or C—R; and the claim defines extensive substituent variables, linker options, fused-ring options, and allowed classes for R groups.
Selected enumerated pyridine-3-carboxamide compounds
A compound selected from enumerated substituted pyridine-3-carboxamide structures, including stereochemical variants and diverse substituent patterns on the pyridine core, aryl/heteroaryl groups, and carboxamide nitrogen substituents.
Pharmaceutically acceptable salt and solvate forms
The selected compounds are optionally provided as pharmaceutically acceptable salts or solvates.
Pharmaceutical composition including excipients
A pharmaceutical composition comprising a selected compound from the claimed set, or a pharmaceutically acceptable salt or solvate, together with at least one pharmaceutically acceptable excipient.
Method of treating hyperinsulinemia by administration
A method for treating hyperinsulinemia in a mammal by administering a selected compound from the claimed set, or a pharmaceutically acceptable salt or solvate, to a mammal in need.
Overall, the claims cover a broad Formula (I) substituted pyridine-carboxamide framework and selected enumerated substituted pyridine-3-carboxamide compounds, each optionally as pharmaceutically acceptable salts or solvates. The claim set further extends to pharmaceutical compositions and to administration-based treatment of hyperinsulinemia in a mammal.
Stated Advantages
Treating hyperinsulinemia in a mammal by administering a compound of the invention.
Biological activity/selectivity is demonstrated using SSTR assays based on cAMP assays.
Microsomal stability is assessed for the compound class.
Activity/selectivity is assessed using a SUR1−− hyperinsulinism model.
Documented Applications
Hyperinsulinemia treatment in a mammal by administering a compound selected from the enumerated substituted pyridine-3-carboxamide structures, including pharmaceutically acceptable salt or solvate forms.
A pharmaceutical composition comprising the selected compound together with at least one pharmaceutically acceptable excipient.
SSTR cAMP assays, including SST5 receptor and SST2 receptor assessment.
Liver microsomal stability assessment.
SUR1−− hyperinsulinism model assessment.
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