4-amino-3-phenylamino-6-phenylpyrazolo[3,4-d]pyrimidine derivatives for use as BCRP inhibitors in therapeutic treatments
Inventors
RUMP, Steffen • Weigt, Henning
Assignees
Dritte Patentportfolio Beteiligungs GmbH and Co KG • Scandion Oncology AS
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Publication Number
US-10975079-B2
Publication Date
2021-04-13
Expiration Date
Abstract
The present invention relates to 5-amino-3-phenylamino-6-phenylpyrazolo[3,4-d]pyrimidine derivatives of the general formula (I) or pharmaceutically acceptable salts or propharmacons thereof for use as BCRP inhibitors, wherein at least one hydrogen atom in at least one of the phenyl groups A and B is substituted by a substituent RH, which has a Hammett constant σp greater than 0.23. For corresponding compounds, surprisingly a particularly high inhibitory activity against BCRP has been discovered which can be exploited for suppressing the multidrug resistance modulator BCRP, thus providing an improvement in efficacy of BCRP affected drugs. This has useful implications for cancer and HIV treatment.
Core Innovation
The patent describes substituted 4-amino-3-phenylamino-6-phenylpyrazolo[3,4-d]pyrimidine derivatives as BCRP (ABCG2, Breast Cancer Resistance Protein) inhibitors. The problem addressed is improving the efficacy of a pharmaceutically active agent where the pharmaceutically active agent is a BCRP substrate, particularly for treatment of cancer and HIV. BCRP is described as being involved in efflux and barrier functions that can limit efficacy of BCRP substrate drugs.
A key aspect is selecting substituents on phenyl rings A and B according to a Hammett-constant criterion for substituents of the phenyl rings, including a requirement that the substituents satisfy a Hammett constant criterion (σp>0.23). This selection is presented as yielding compounds with high BCRP specificity. The document also describes a relationship between BCRP inhibition and co-administration, including evaluation of whether a co-administered agent is a BCRP substrate.
The patent further characterizes compound suitability in multidrug resistance modulation by using determination approaches based on efflux ratio and FTC, including discussion of net efflux ratio thresholds. It states advantages relative to broad-spectrum MDR inhibitors and discusses transporter selectivity, including P-gp (ABCB1) effects. Example compounds and reported in vitro inhibition and DMPK/tox-related observations are provided, including IC50 values and statements about lack of significant CYP inhibition/induction behavior.
Claims Coverage
The independent claim is directed to a method for increasing the efficacy of a pharmaceutically active agent for treatment of cancer by co-administering a BCRP-directed compound. The inventive features focus on: (i) co-administration to increase efficacy compared to administering the active agent without the compound, and (ii) the requirement that the pharmaceutically active agent is a BCRP substrate. Dependent claims further narrow the method by specifying BCRP transporter inhibition and quantitative net efflux ratio constraints.
Co-administration increases efficacy of a BCRP substrate cancer agent
Administering the pharmaceutically active agent to the patient and administering an amount of a compound of formula (or a pharmaceutically acceptable salt thereof), where the pharmaceutically active agent is a BCRP substrate and the amount of the compound is effective in increasing the efficacy of the pharmaceutically active agent as compared to the efficacy when the pharmaceutically active agent is administered without the compound.
Inhibition of BCRP transporter activity
The amount of the compound inhibits BCRP transporter activity in the patient.
Net efflux ratio threshold (at least 2)
The pharmaceutically active agent has a net efflux ratio of at least 2.
Net efflux ratio threshold (5 or more)
The pharmaceutically active agent has a net efflux ratio of 5 or more.
Use with specified cytostatic agent classes
The pharmaceutically active agent is a cytostatic agent selected from cytostatic anthrachinone, cytostatic anthracycline, cytostatic antimetabolite, cytostatic campothecin, or cytostatic Epipodophyllotoxin.
Irinotecan as the BCRP substrate active agent
The pharmaceutically active agent is Irinotecan.
Overall, the claim set centers on increasing cancer efficacy by co-administering a compound of formula (or its pharmaceutically acceptable salt) with a pharmaceutically active agent that is a BCRP substrate, with dependent claims requiring BCRP transporter inhibition and specifying net efflux ratio thresholds and particular categories or named examples of cytostatic BCRP substrate drugs.
Stated Advantages
Improved efficacy/safety relative to broad-spectrum MDR inhibitors.
Reduced P-gp effects compared with broad-spectrum MDR inhibitors.
High BCRP specificity.
Documented Applications
Increasing the efficacy of a pharmaceutically active agent for the treatment of cancer in a patient in need thereof where the pharmaceutically active agent is a BCRP substrate.
Therapeutic use in cancer therapy and HIV is described in the patent content provided.
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