Phenothiazine derivatives and uses thereof
Inventors
Bumcrot, David A. • Sehgal, Alfica • Hertzog, Donald L.
Assignees
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Publication Number
US-12145963-B2
Publication Date
2024-11-19
Expiration Date
Abstract
The present invention provides phenothiazine compounds, processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment of various diseases or conditions, for example ribosomal disorders and ribosomopathies, e.g. Diamond Blackfan anemia (DBA).
Core Innovation
The disclosure relates to phenothiazine compounds defined by formula variants including formula (Ia), formula (II), formula (III), formula (IIIa), formula (IV), and formula (V), with defined R-group selections and ring constraints. The structural framework constrains substituent options and embodiment ranges, including parameters n and m, and includes phenothiazine cores and substituted phenothiazines.
The compounds are described as formula (II) or pharmaceutically acceptable salts thereof, with R1 selected from hydrogen, —OH, and C1-6 alkoxy; R2 selected from C1-6 alkyl substituted with one or more substituents independently selected from —OH, C1-6 alkoxy, —C(O)NRaRb, —C(O)Rc, —C(O)ORd, S(O)2C1-6 alkyl, and S(O)2NRaRb; and R3 selected from hydrogen or C1-6 alkyl. Ra, Rb, Rc, and Rd are each independently hydrogen or C1-6 alkyl, with n selected from 1 or 2 and m selected from 1, 2, or 3.
The disclosure frames these phenothiazine compounds as calmodulin-binding inhibitors or antagonists and reports calmodulin binding and calmodulin inhibition activity. It also discusses cell permeability and efflux-related assessments, zebrafish phenotype grouping, and disease-relevant outcomes associated with rescue of ribosomal disorder and ribosomopathy phenotypes.
Claims Coverage
The provided claims coverage centers on one independent claim for a compound of formula (II) and pharmaceutically acceptable salts, constrained by defined substituent choices and ring parameters. Across the inputs, the inventive features consistently focus on the same formula (II) scaffold and its variable groups.
Formula (II) phenothiazine compound definition
A compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from hydrogen, —OH, and C1-6 alkoxy; R2 is C1-6 alkyl substituted with one or more substituents each independently selected from —OH, C1-6 alkoxy, —C(O)NRaRb, —C(O)Rc, —C(O)ORd, S(O)2C1-6 alkyl, and S(O)2NRaRb; R3 is hydrogen or C1-6 alkyl; Ra, Rb, Rc, and Rd are each independently hydrogen or C1-6 alkyl; n is 1 or 2; and m is selected from 1, 2, or 3.
Pharmaceutically acceptable salts of the formula (II) compound
The compound of formula (II) together with a pharmaceutically acceptable salt thereof.
The claim coverage is limited to the formula (II) phenothiazine scaffold with specifically constrained substituent sets for R1 through R3 and Ra through Rd, defined integer limits for n and m, and pharmaceutically acceptable salts.
Stated Advantages
Rescues DBA phenotypes.
Reduced BBB permeability compared to trifluoperazine.
Reduced dyskinesia/extrapyramidal effects compared to trifluoperazine.
Improves erythroid outcomes by increasing CD71+ erythroid cells and hemoglobin.
Decreases p21 in CD34+ erythroid populations.
Documented Applications
Treatment of ribosomal disorders/ribosomopathies, including Diamond-Blackfan anemia (DBA).
Treatment context including zebrafish rps29 as a model associated with DBA phenotype rescue.
Patient/genotype-related examples including cases associated with RPS19 or other ribosomal protein (RP) mutations, myelodysplasia including 5q-MDS, Shwachman-Diamond syndrome (SDS) with SBDS, and Treacher-Collins syndrome (TCS) with TCOF1.
Potential combination therapy with standard DBA regimens and other calmodulin inhibitors.
Treating gastrointestinal diarrhea, including travelers’ diarrhea and secretory diarrhea.
Treating cardiovascular structural disease.
Treating neurodegeneration, including Alzheimer’s disease.
Treating autoimmune disorders, including autoimmune encephalomyelitis and lupus-like disease.
A pharmaceutical composition comprising a compound of formula (Ia) and an excipient.
Calmodulin (CaM) binding assessment using a fluorescence polarization assay, with IC50 values reported for MT compounds.
Cell permeability and efflux-related assessment using Caco-2 and MDCK-MDR1, including reported efflux ratios and permeability coefficient (Papp).
Zebrafish Rps29 heterozygote assay described via phenotype grouping results, including evaluation using Z' factor.
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