1 H-pyrazol-1-yl-thiazoles as inhibitors of lactate dehydrogenase and methods of use thereof
Inventors
Maloney, David J. • Waterson, Alex Gregory • Bantukallu, Ganesha Rai • Brimacombe, Kyle Ryan • Christov, Plamen • Dang, Chi V. • DARLEY-USMAR, Victor M. • Hall, Matthew • Hu, Xin • Jadhav, Ajit • Jana, Somnath • Kim, Kwangho • Moore, William J. • Mott, Bryan T. • Neckers, Leonard M. • Simeonov, Anton • Sulikowski, Gary Allen • Urban, Daniel Jason • Yang, Shyh Ming
Assignees
UAB Research Foundation • University of Pennsylvania Penn • Vanderbilt University • National Institutes of Health NIH
Publication Number
US-10954228-B2
Publication Date
2021-03-23
Expiration Date
2037-06-29
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Abstract
The disclosure provides a compound of the formula (II) and pharmaceutically acceptable salts thereof. The variables, e.g. n, R, R3, R10, X, Y, and Z are defined herein. These compounds act as lactate dehydrogenase inhibitors and are useful for treating cancer and fibrosis. The compounds may be particularly useful for treating forms of cancer in which a metabolic switch from oxidative phosphorylation to glycolysis has occurred. The disclosure also provides pharmaceutical compositions containing a compound of this formula and method for treating patients having cancer, fibrosis, or other conditions in which a metabolic switch from oxidative phosphorylation to glycolysis has occurred.
Core Innovation
The invention provides compounds of formula (II), as defined herein, which act as inhibitors of lactate dehydrogenase A (LDHA) and/or lactate dehydrogenase B (LDHB). These compounds and their pharmaceutically acceptable salts are effective in inhibiting LDH activity, with potential therapeutic applications in treating cancer and fibrosis. The compounds are designed to be selective for LDHA and/or LDHB relative to other dehydrogenases and possess favorable solubility, permeability, and pharmacokinetic profiles suitable for anti-cancer agents.
The problem being solved addresses the need for novel LDH inhibitors that exhibit improved potency, selectivity, and bioavailability compared to previously known LDHA inhibitors such as gossypol and certain quinolinyl derivatives, which have shown poor in vivo bioavailability. Given the pivotal role of LDH in the Warburg effect and cancer cell metabolism, inhibiting LDH offers a promising approach to reduce glucose metabolism, tumor cell proliferation, and tumor growth. Additionally, LDH inhibitors have utility in treating fibrosis, including idiopathic pulmonary fibrosis, and in overcoming resistance to existing anti-cancer agents by re-sensitizing cancer cells.
Claims Coverage
The patent includes one independent claim defining the compound of formula (II) and its salts, and further claims related to pharmaceutical compositions and methods of inhibiting LDHA/LDHB and treating fibrosis or cancer using these compounds.
Compound of formula (II) as LDH inhibitor
The compound is defined by formula (II) with specified substituents including X as hydrogen or halogen; Y as hydrogen or C1-C2alkyl; Z as carboxylic acid, amides, trifluoromethyl derivatives, hydroxymethyl or boronic acid groups; n from 0 to 3; R as halogen, hydroxyl, alkyl or alkoxy; R3 as various substituted or unsubstituted rings or groups including phenyl, indanyl, heterocycles, or -L-Q structures with specified L and Q; and R10 as (cyclopropyl)alkyl or substituted cyclopropyl derivatives. These compounds are lactate dehydrogenase A and/or B inhibitors.
Pharmaceutical composition comprising the compound
A pharmaceutical composition containing at least one compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
Method of inhibiting LDHA and/or LDHB activity
A method of inhibiting lactate dehydrogenase A or B activity in a cell by administering a compound of formula (II) or salt thereof, resulting in inhibited enzyme activity.
Method of treating fibrosis or cancer
A method for treating fibrosis, including idiopathic pulmonary fibrosis, or cancer in a patient by administering an effective amount of the compound of formula (II) or salt.
Method of treating resistant cancer cells
A method of treating patients with cancer cells resistant to an anti-cancer agent by administering a compound of formula (II) or salt together with the anti-cancer agent, where the compound re-sensitizes the cancer cells to the anti-cancer agent.
The claims cover the novel chemical entities of formula (II) with defined substituents as potent LDHA/LDHB inhibitors, pharmaceutical compositions thereof, and methods of treating cancer and fibrosis including drug-resistant cancer by utilizing these compounds, demonstrating significant therapeutic potential.
Stated Advantages
The compounds exhibit improved potency, selectivity for LDHA and/or LDHB over other dehydrogenases, and enhanced bioavailability compared to prior art inhibitors.
They are useful in treating diseases characterized by metabolic switching to glycolysis, such as cancer and fibrosis, including idiopathic pulmonary fibrosis.
The compounds can re-sensitize cancer cells resistant to anti-cancer agents, thereby improving therapeutic response.
Documented Applications
Treatment of cancer types characterized by a metabolic switch from oxidative phosphorylation to glycolysis, including various solid tumors and leukemias.
Treatment of fibrosis, especially idiopathic pulmonary fibrosis.
Combination therapy with anti-cancer agents to re-sensitize resistant cancer cells to treatment.
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