Substituted quinoline analogs as aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors
Inventors
Yang, Shyh Ming • Maloney, David J. • MARTINEZ, Natalia • YASGAR, Adam • Simeonov, Anton • VASILIOU, Vasilis
Assignees
Yale University • Office of Technology Transfer
Publication Number
US-11505559-B2
Publication Date
2022-11-22
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 present disclosure provides compounds of Formula I and their pharmaceutically acceptable salts which act as aldehyde dehydrogenase inhibitors, particularly targeting aldehyde dehydrogenase 1A1 (ALDH1A1). These compounds are designed for therapeutic use, capable of inhibiting ALDH1A1 enzymatic activity, and come with pharmaceutical compositions containing them. The invention further includes methods of treating disorders associated with ALDH1A1, by administering effective amounts of these compounds to patients in need.
Aldehyde dehydrogenases (ALDH) comprise a family of enzymes that oxidize cytotoxic aldehydes, with at least 19 isozymes exhibiting differing substrate specificities and cellular locations. ALDH1A1, a member of this family, is recognized as a cancer stem cell marker; its overexpression correlates with poor prognosis in multiple malignancies and contributes to tumor aggressiveness and resistance to chemotherapy and radiation. The invention addresses the need for specific ALDH1A1 inhibitors, as previous research shows ALDH1A1 is a primary target for drug development to enhance therapeutic efficacy in cancer treatment.
Besides cancer, ALDH1A1 is implicated in metabolism and obesity, being predominantly expressed in white adipose tissue, where its knockdown in murine models limits weight gain and improves glucose homeostasis. Inhibitors of ALDH1A1, therefore, hold potential as anti-obesity agents. Overall, the disclosure aims to solve the problem of developing selective ALDH1A1 inhibitors for the treatment of a variety of conditions including cancer, inflammation, and obesity, providing new therapeutic options through chemical entities of Formula I.
Claims Coverage
The patent includes multiple independent claims focusing on compounds of specific formulae and their use in pharmaceutical compositions and methods of treatment. The main inventive features cover the compounds' structural characteristics and their therapeutic applications.
Compounds of Formula I-1 and related subformulae
The claims cover compounds or salts of Formula I-1 and related subformulae (such as Formula I-A, I-B, and variations), featuring specific structural features including heterocyclic rings, variable substitutions at defined positions (R1, R3, R5, Y, etc.), and particular functional groups that provide inhibition of aldehyde dehydrogenase 1A1.
Specific substituents and ring formations at variable positions
Certain claims specify that R1 can be (CN)C(CH3)2— and that Y can be CR1R2 with R1/R2 taken together to form various cycloalkyl or heterocycloalkyl rings optionally substituted with halogen, hydroxyl, oxo, or alkyl groups. Additional claims specify Y as SO2 or NR1 with defined substituents, and R3 as fluoro, trifluoromethyl, or alkyl substituents.
Pharmaceutical compositions comprising the compounds
The patent claims pharmaceutical compositions that include a pharmaceutically acceptable carrier combined with a compound of Formula I, either alone or in combination with other active agents, suitable for therapeutic administration.
Methods of treating ALDH1A1 associated disorders
Claims include methods for treating disorders associated with ALDH1A1, such as cancer, inflammation, obesity, and related diseases, by administering therapeutically effective amounts of compounds of Formula I to subjects in need.
Collectively, the claims define the chemical entities of Formula I with specific structural and substitutional features, pharmaceutical compositions containing these compounds, and therapeutic methods for treating ALDH1A1 related diseases, emphasizing selective inhibition and clinical applications.
Stated Advantages
Compounds demonstrate low-nM inhibition and excellent selectivity for ALDH1A1.
They provide therapeutic potential for enhancing the efficacy of chemotherapy and radiation in cancer treatment.
ALDH1A1 inhibitors offer potential as anti-obesity agents by modulating metabolism and glucose homeostasis.
Documented Applications
Treatment of a variety of 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, estrogen-dependent growth of uterine fibroids, and breast cancer.
Treatment of disorders associated with inflammation 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 acquired chemoresistance and lysosomal autophagy in cancer cells.
Treatment of obesity and related metabolic disorders.
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