Substituted quinoline analogs as aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors
Inventors
Yang, Shyh Ming • Maloney, David J. • MARTINEZ, Natalia • YASGAR, Adam • Simeonov, Anton
Assignees
US Department of Health and Human Services
Publication Number
US-11795177-B2
Publication Date
2023-10-24
Expiration Date
2038-10-30
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Abstract
The disclosure provides compounds of Formula I, which may be useful as aldehyde dehydrogenase inhibitors and the pharmaceutically acceptable salts thereof. The variables, J, R4, G, Q, and ring A are defined herein. Aldehyde dehydrogenase inhibitors of Formula I are useful for treating a variety of conditions including cancer and inflammation. The disclosure includes methods for using compounds and salts of Formula I to treat colon cancer, pancreatic cancer, nasopharyngeal carcinoma, thyroid cancer, prostate cancer, ovarian cancer, head and neck squamous cell carcinoma, lung cancer, hepatocellular carcinoma, leukemia, brain tumors breast cancer, atherosclerosis, ischaemic heart disease, acne vulgaris, asthma, autoimmune diseases, autoinflammatory diseases, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis, and interstitial cystitis. The disclosure also includes pharmaceutical compositions containing a compound or salt of Formula I.
Core Innovation
The invention provides compounds of Formula I and their pharmaceutically acceptable salts, useful as aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors. These compounds are defined by variable groups such as J, R4, G, Q, and ring A with specific structural characteristics, which inhibit ALDH1A1 enzymatic activity. The patent discloses pharmaceutical compositions containing these compounds and methods of treating disorders related to ALDH1A1 activity.
The problem addressed arises from the role of ALDH1A1 in various human cancers and other conditions. ALDH1A1 is a cancer stem cell marker associated with poor prognosis, tumor aggressiveness, and resistance to chemotherapy and radiation. Existing inhibitors lacked specificity and efficacy. Additionally, ALDH1A1 is involved in metabolism and obesity by its predominant expression in white adipose tissue, influencing weight gain and glucose homeostasis. Hence, there is a need for specific ALDH1A1 inhibitors capable of treating cancer, inflammation, obesity, and related disorders.
Claims Coverage
The patent includes multiple claims describing the compounds of Formula I-2 and their specific structural features, pharmaceutical compositions thereof, and methods of treatment. The independent claims focus on chemical structure and therapeutic applicability of the compounds.
compounds of Formula I-2 with specific R1 and R2 substituents
The compounds are characterized by the presence of R1 and R2 substituents where R1 can be hydrogen, halogen, hydroxyl, cyano, —CF3, C1-C4alkyl optionally substituted, and other specified substituents; R2 can be methyl or other specified groups. The compounds may include substitution patterns on the A-ring with chloro, fluoro, methyl, or methoxy groups. Variations also include the presence or absence of substituents such as fluoro, trifluoromethyl, and C1-C3alkyl on position R3.
use of pharmaceutically acceptable salts and specific subformulae
The compounds also encompass pharmaceutically acceptable salts and specific subformulae including but not limited to Formula I-S, I-T, I-U, I-V, I-W, I-Y with defined variable groups R11, R12, and R13, facilitating specificity and efficacy.
pharmaceutical compositions containing compounds of Formula I-2
Pharmaceutical compositions comprising the compounds or their salts along with pharmaceutically acceptable carriers are claimed for therapeutic use.
methods of treatment using the compounds
Methods of treating ALDH1A1 associated disorders, including various cancers, inflammation, and obesity, are claimed by administering effective amounts of the described compounds.
The claims collectively cover novel substituted quinoline derivatives as ALDH1A1 inhibitors characterized by specific substituents and ring structures, pharmaceutical compositions comprising these compounds, and methods for treating ALDH1A1-related diseases, providing a comprehensive coverage of chemical entities and their therapeutic applications.
Stated Advantages
Compounds demonstrate low nanomolar inhibition of ALDH1A1 and excellent selectivity.
Inhibition of ALDH1A1 can enhance the efficacy of chemotherapy and radiation by targeting cancer stem cells and overcoming drug resistance.
ALDH1A1 inhibitors have utility in treating obesity by modulating metabolism and glucose homeostasis.
Methods provide therapeutic benefit for a wide range of cancers, inflammatory diseases, and metabolic disorders.
Documented Applications
Treatment of various cancers including colon cancer, pancreatic cancer, nasopharyngeal carcinoma, thyroid cancer, prostate cancer, ovarian cancer, head and neck squamous cell carcinoma, lung cancer, hepatocellular carcinoma, leukemia, brain tumors, breast cancer, and uterine fibroids.
Treatment of inflammatory diseases and conditions such as atherosclerosis, ischaemic heart disease, acne vulgaris, asthma, autoimmune diseases, autoinflammatory diseases, celiac disease, chronic prostatitis, glomerulonephritis, hypersensitivities, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis, and interstitial cystitis.
Treatment of metabolic disorders including obesity and diabetes.
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