Caspase inhibitors
Inventors
Thomas, Craig • Boxer, Matthew B.
Assignees
US Department of Health and Human Services
Publication Number
US-9365612-B2
Publication Date
2016-06-14
Expiration Date
2031-01-27
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Abstract
A compound, or a pharmaceutically acceptable salt or ester thereof, of formula I: X—W wherein X is a caspase-selective structure and W has the structure of —NH—CH(Y)(Z) wherein Y is a structure that can form a reversible covalent bond with a caspase; and Z is selected from a carboxyl moiety or a carboxylic acid mimetic.
Core Innovation
The invention discloses compounds and pharmaceutical compositions that function as caspase inhibitors, especially targeting caspase 1. The compounds have a formula consisting of a caspase-selective structure (X) linked to a warhead (W) having the structure —NH—CH(Y)(Z), where Y enables formation of a reversible covalent bond with caspases, and Z is a carboxyl moiety or a carboxylic acid mimetic. These compounds are designed to reversibly inhibit the proteolytic activity of pro-inflammatory caspases, thus preventing the activation of cytokines such as interleukin 1β and interleukin 18.
The caspase-selective structure X comprises amino acid residues or peptide mimetics designed to confer specificity and selectivity among caspases, with particular embodiments specific for caspase 1. The warhead, which includes groups such as cyano or boronic acid, forms a reversible covalent bond with the catalytic cysteine residues of caspases. Novel chemical motifs such as a 3-cyanopropanyl moiety have been incorporated to improve potency and stability relative to known inhibitors like VX-765.
The problem addressed is the need for effective caspase 1 inhibitors for therapeutic intervention in ischemic disorders, neurodegenerative diseases, autoimmune and inflammatory diseases, among others. Existing caspase 1 inhibitors such as VX-765 have limitations including moderate stability and specificity. This invention aims to provide novel compounds with enhanced inhibitory potency, selectivity, aqueous stability, and favorable pharmacokinetic properties to improve therapeutic efficacy and avoid degradation issues faced by earlier agents.
Claims Coverage
The patent includes two independent claims that cover composition of matter aspects of compounds with specific structural formulas and pharmaceutical compositions comprising such compounds. These claims define novel caspase inhibitors characterized by structural features that provide reversible covalent inhibition and selectivity.
Specific structural formula for caspase inhibitors
Compounds of formula II comprising specific substituents where R1, R2, R3, R4, R5, R6, R8, R9, R20, and R21 are selected from defined groups, including features that enable reversible covalent binding to caspases. The compounds include at least one cyano group and have peptide-mimetic and warhead components tailored for specificity and reversible covalent bonding.
Specific sub-formula embodiments with defined structures
Compounds of formula III, representing particular embodiments with specified amino acid residues and substituents that confer potent caspase inhibition. These include defined heterocyclic substituents and arrangements that optimize inhibitory activity.
Potent caspase inhibition with biochemical and physicochemical properties
Compounds having caspase inhibition IC50 values under 100 nM, exhibiting aqueous solubility over 10 μg/mL, LogD lower than 5, and molecular weight below 650 daltons, thereby combining potency with favorable drug-like properties.
Pharmaceutical compositions with therapeutically effective amounts
Pharmaceutical compositions comprising therapeutically effective amounts of the disclosed compounds with pharmaceutically acceptable additives, enabling therapeutic use in treating caspase-mediated conditions.
The independent claims cover inventive compounds defined by specific structural formulas with reversible covalent warheads targeting caspases, especially caspase 1, exhibiting potent inhibition and favorable drug properties. The claims also include pharmaceutical compositions comprising these compounds for therapeutic application.
Stated Advantages
The compounds exhibit potent inhibition of caspase 1 with IC50 values significantly lower than known inhibitors.
The compounds demonstrate improved aqueous stability under neutral, acidic, and basic conditions compared to previous agents such as VX-765.
High selectivity for caspase 1 over other caspase family members, reducing potential off-target effects.
Favorable in vitro absorption, distribution, metabolism, and excretion (ADME) profiles, including moderate microsomal stability and protein binding.
Documented Applications
Treatment of caspase-mediated conditions including IL-1-, apoptosis-, IL-18-, or IFN-γ-mediated diseases.
Therapeutic use in inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative diseases, infectious diseases, degenerative diseases, and necrotic diseases.
Specific diseases listed include rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, sepsis, psoriasis, Alzheimer's disease, Huntington's disease, acute and chronic pancreatitis, asthma, myocardial ischemia, and multiple sclerosis among others.
Use in methods of inhibiting caspase 1, 4, 5, 8, 9, 10, or 14 activity in biological samples.
Commercial reagents for biochemical or cellular assays to detect or isolate caspases.
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