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 Nck AS, Precision Pharmaceuticals Inc, New England Digital Corp invention works as followsThe 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?):” ):Click here to view the patent on Google Patents.