Compounds for the prevention and treatment of cardiovascular diseases
Inventors
Assignees
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Publication Number
US-9199990-B2
Publication Date
2015-12-01
Expiration Date
Abstract
The present disclosure relates to compounds, which are useful for regulating the expression of apolipoprotein A-I (ApoA-I), and their use for treatment and prevention of cardiovascular disease and related disease states, including cholesterol- or lipid-related disorders, such as, for example, atherosclerosis.
Core Innovation
The disclosure relates to compounds of Formula II, including pharmaceutically acceptable salts, having defined substituent selections and structural constraints expressed through parameters X, Y, R1-R10, W/p, and Z1-Z3. The structural definitions constrain ring/linkage features and substituent classes via multiple provisos, and the disclosed subject matter includes substituted quinazolinone and related heteroaryl compounds, including quinazolin-4(3H)-one, quinazolinone, pyridopyrimidinone, and naphthyridinone derivatives.
The invention provides medical uses for the Formula II compounds in mammals, specifically for treating or reducing the risk of acquiring cardiovascular-, cholesterol-, or lipid-related disorders. The covered disorders are expressed as broad categories, and the therapeutic method is defined as administering a therapeutically effective amount of a Formula II compound or a pharmaceutically acceptable salt thereof.
The disclosure also includes methods for increasing levels of high density lipoprotein cholesterol (HDL-C) and states treatment-related contexts involving ApoA-I. The patent ties Formula II compound administration to HDL-C and ApoA-I elevation, including ApoA-I mRNA induction and ApoA-I and HDL-C plasma levels in hApoA-I transgenic and wild-type mice.
Claims Coverage
The claim set centers on therapeutic methods that administer Formula II compounds, or pharmaceutically acceptable salts thereof, with independent claims directed to treating or reducing risk of cardiovascular-, cholesterol-, or lipid-related disorders and one independent claim directed to increasing HDL-C levels. The inventive scope is defined by extensive Formula II structural constraints on X, Y, R1-R10, W/p, and Z1-Z3, plus conditional provisos and, in some claims, specified Formula II compound embodiments.
Formula II compounds for treating or reducing risk of cardiovascular-, cholesterol-, or lipid-related disorders
A method of treating or reducing the risk of acquiring a cardiovascular-, cholesterol-, or lipid-related disorder in a mammal by administering a therapeutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt thereof, with X, Y, R1-R10, W/p, and Z1-Z3 constrained by the recited selections and provisos.
Selected Formula II compounds for treating or reducing risk
A method of treating or reducing the risk of acquiring a cardiovascular-, cholesterol-, or lipid-related disorder in a mammal by administering a therapeutically effective amount of a compound selected from a specified list of Formula II and related quinazolinone compounds, together with pharmaceutically acceptable salts thereof.
Formula II compounds for increasing HDL-C levels
A method of increasing levels of high density lipoprotein cholesterol (HDL-C) in a mammal by administering a therapeutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt thereof, with X, Y, R1-R10, W/p, and Z1-Z3 constrained by the recited selections and provisos.
Overall, the claims cover therapeutic use of Formula II compounds, including selected Formula II members, for cardiovascular-, cholesterol-, or lipid-related disorders and for increasing HDL-C levels, with the scope controlled by detailed structural and conditional limitations.
Stated Advantages
Treating or reducing the risk of acquiring a cardiovascular-, cholesterol-, or lipid-related disorder in a mammal.
Increasing levels of high density lipoprotein cholesterol (HDL-C) in a mammal.
Increasing ApoA-I levels.
Increases ApoA-I mRNA in assays meeting the "Active" criterion.
Provides an HDL-C/ApoA-I elevation framework for in vivo efficacy.
Documented Applications
ApoA-I induction in HepG2 cells and primary human hepatocytes [procedural detail omitted for safety].
Assessment of ApoA-I and HDL-C plasma levels in hApoA-I transgenic and wild-type mice [procedural detail omitted for safety].
Prevention or treatment of cardiovascular diseases including atherosclerosis via HDL-C/ApoA-I raising.
A method of treating or reducing the risk of acquiring cardiovascular-, cholesterol-, or lipid-related disorders in a mammal by administering Formula II compounds or pharmaceutically acceptable salts.
A method of increasing levels of high density lipoprotein cholesterol (HDL-C) in a mammal by administering Formula II compounds or pharmaceutically acceptable salts.
Assay-based evaluation using ApoA-I mRNA quantification criteria and subsequent ApoA-I mRNA/protein induction.
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