Invented by Eric B. Sjogren, Jim Li, Lijing Chen, Roland J. Billedeau, Timothy F. Stanton, Michael Van Zandt, Darren Whitehouse, Gunnar E. Jagdmann, Jr., Lene Raunkjaer PETERSEN, Nck AS, Precision Pharmaceuticals Inc, New England Digital Corp

The market for compositions for inhibiting arginase activity has been steadily growing in recent years. Arginase is an enzyme that plays a crucial role in the urea cycle, converting arginine into ornithine and urea. While arginase is essential for normal physiological functions, its overexpression or dysregulation has been linked to various diseases and conditions, including cardiovascular diseases, cancer, and immune disorders. Inhibiting arginase activity has emerged as a promising therapeutic strategy to combat these diseases. By blocking the enzyme’s function, the production of ornithine is reduced, leading to a decrease in the synthesis of polyamines and nitric oxide, which are involved in cell proliferation, inflammation, and immune response. Consequently, inhibiting arginase activity can help regulate these processes and potentially alleviate the symptoms associated with arginase-related diseases. The market for compositions targeting arginase activity is primarily driven by the increasing prevalence of diseases where arginase dysregulation is implicated. Cardiovascular diseases, such as hypertension and atherosclerosis, are major contributors to global morbidity and mortality. Studies have shown that arginase overexpression in vascular endothelial cells can impair nitric oxide production, leading to endothelial dysfunction and the development of cardiovascular diseases. Therefore, there is a growing demand for compositions that can effectively inhibit arginase activity and restore normal endothelial function. Cancer is another significant area where the market for arginase inhibitors is expanding. Tumor cells often exhibit elevated arginase expression, which helps them evade immune surveillance and promote tumor growth. By inhibiting arginase activity, the tumor microenvironment can be altered, leading to enhanced immune response against cancer cells. This has sparked interest in developing arginase inhibitors as potential adjuvants for cancer immunotherapy. Furthermore, arginase dysregulation has been implicated in immune disorders, such as asthma and autoimmune diseases. In asthma, arginase overexpression in airway smooth muscle cells contributes to airway hyperresponsiveness and inflammation. By inhibiting arginase activity, the production of nitric oxide can be restored, leading to improved lung function and reduced inflammation. This has fueled the demand for compositions that can effectively target arginase activity in the respiratory system. In terms of market players, pharmaceutical companies and research institutions are actively engaged in developing compositions for inhibiting arginase activity. Various approaches are being explored, including small molecule inhibitors, natural compounds, and gene therapy techniques. Several arginase inhibitors have already entered clinical trials, demonstrating promising results in preclinical studies. As the understanding of arginase dysregulation and its implications in various diseases continues to grow, the market for compositions targeting arginase activity is expected to expand further. The potential therapeutic benefits of inhibiting arginase activity make it an attractive avenue for drug development. However, challenges such as specificity, bioavailability, and safety need to be addressed to ensure the successful translation of these compositions into effective treatments. In conclusion, the market for compositions for inhibiting arginase activity is witnessing significant growth due to the increasing prevalence of diseases associated with arginase dysregulation. The potential therapeutic benefits of targeting arginase activity make it an attractive area for drug development. With ongoing research and development efforts, the market is expected to expand further, offering new treatment options for patients suffering from arginase-related diseases.

The Nck AS, Precision Pharmaceuticals Inc, New England Digital Corp invention works as follows

The disclosure is a novel class compounds with activity inhibitory activity towards arginase and pharmaceutical compositions containing the compounds. The disclosure also includes methods for treating cancer using the arginase-inhibitors.

Background for Compositions for inhibiting arginase Activity

Cancer is the uncontrolled proliferation of cells within the body that leads to invasion of vital organs and, often, death. In the beginning, pharmacological cancer treatment used non-specific cytotoxic drugs that attacked all rapidly dividing cell types, including normal ones. The non-specific cytotoxic drugs have anti-tumor properties, but are often restricted in their use due to severe side effects. “As our understanding of the proteins, pathways and other factors that allow cancer cells to flourish has developed, more targeted agents that block specific proteins in cancer cells have been developed.

Immuno-oncology is a new field that has emerged to address the challenges of treating cancers. It’s also known as tumor immunology. Certain tumors have developed mechanisms that allow them to avoid destruction by the immune system. Tumor immunology focuses on activating your body’s immune system in order to kill and attack tumors. In tumor immunology, the naturally occurring amino acids arginine and lysine are important because they promote growth and survival in the body’s cancer fighting cytotoxic T cells. Arginase is an enzyme secreted and produced by neutrophils, myeloid-derived suppressor cells, and other cancer patients. Arginase levels were elevated in plasma from patients with renal cell carcinoma, breast, chronic myelogenous, lung, esophageal, prostate, glioblastoma and acute myeloid cancer. There is therefore a need to create inhibitors of arginase which restore arginine in the tumor microenvironment and promote the tumor-killing ability of cytotoxic cells.

In certain embodiments, this disclosure provides a set of compounds that are useful in inhibiting arginase. The compounds disclosed have a formula (I).

Or a pharmaceutically accepted salt thereof

wherein the following definitions of Rb, X and R1, R2, are given in the discussion below on the disclosure section.

In certain embodiments, “the

The “structure” in compounds of formula I represents an alpha amino acid residue. X?O is optionally replaced with R3, and the terminal ammonia can be substituted by R3. In these embodiments, the R1 group represents an alpha amino acid side chain. The amino acid side chain can be of either naturally occurring or non-natural amino acids. In some embodiments, R1 can be an amino acid side-chain of Arg His Lys Asp Glu Ser Thr Asn Gln Cys Sec Gly Ala Val Ile Leu Met Phe Tyr Trp or Trp. In some embodiments, the amino acid side chain R1 is Gly, Ala or Ser. R1 can take either the R- or S configuration in such embodiments.

In certain embodiments, the disclosure provides pharmaceutical compositions that include a compound from the disclosure and an acceptable pharmaceutical carrier.

In certain embodiments of the disclosure, methods are provided for treating or preventing the cancer by administering a therapeutically-effective amount of a drug or compound composition.

The disclosure also provides methods for treating cancer or preventing it, which include administering an arginase inhibitor of the disclosure in conjunction with one or more additional chemotherapy agents to a patient who is in need.

In specific embodiments, the disclosure offers methods for treating or prevening cancer. These include administering simultaneously to a patient in need of such treatment an arginase-inhibitor of the disclosure, and an inhibitor indoleamine-2,3-dioxygenase. The IDO inhibitor can be a formula disclosed in this document or a substance with a similar structure. The IDO inhibitor can be epacadostat in certain embodiments.

The present disclosure is concerned with compounds and compositions that are useful in inhibiting arginase as well as various therapeutic applications. The inventors focused their previous studies on a small molecule class that included (i) amino acids and (ii), boronic acid-type molecules, like the compounds represented generically by Formula A below. The compounds of Formula A have been found to be useful for the inhibition of arginase.

The inventors were surprised to discover that a compound of Formula A could be isolated by treating it with anhydrous alcohol. This produced a cyclic, alkoxylated, compound (I). Contrary to many prodrugs these cyclic alkoxylated compound of formula I do not require enzymatic processes to reveal their underlying arginase inhibiting compounds. Instead, exposure to water or aqueous environments (e.g. upon oral dosage) will produce the “underlying” compounds. Arginase inhibitors, such as the compound in formula (A), are produced by exposing a compound of formula I to water or an aqueous environment. These cyclic alkoxylated formula (I), compounds, typically, have better processing and handling characteristics, higher purity and greater stability than their uncyclized equivalents.

Compounds” of the Disclosure

The disclosure discloses a compound with a formula I:

Or a pharmaceutically accepted salt thereof

wherein Rb, R1, R2, R3 & R4 are defined as follows

In certain embodiments the disclosure discloses a compound with a formula of (I?):” ):

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