FAAH inhibitors
Inventors
Hudson, Colleen • Barden, Timothy C. • Jia, James • Mermerian, Ara • Peng, Bo • Yang, Jane • Yu, Xiang Y. • Sprott, Kevin • Fretzen, Angelika
Assignees
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Publication Number
US-9657012-B2
Publication Date
2017-05-23
Expiration Date
Abstract
The present disclosure relates to compounds useful as inhibitors of the enzyme Fatty Acid Amide Hydrolase (FAAH). The disclosure also provides pharmaceutically acceptable compositions comprising the compounds of the disclosure and methods of using the compositions in the treatment or prevention of various disorders. Compounds of the invention are described in Table 1.
Core Innovation
The invention relates to compounds selected from Table 1 and pharmaceutically acceptable salts thereof. The disclosed structures are substituted indole/azaindole and related heteroaromatic compounds, including indole/oxoacetamide derivatives, pyrrolopyridine analogs, and other heteroaromatic or aryl moieties with variable halogen, methoxy, alkoxy, amino, heteroaryl, and other substituents.
The disclosure provides specific chemical structures and analogs presented as individual candidate compounds in free base form and as pharmaceutically acceptable salts. The compound sets include fused heteroaromatic ring systems and linked pyridine-like or heteroaryl substituents, with entries numbered across multiple sets and supported by Table 1 compound lists.
The disclosure further states biological evaluation and therapeutic context for the compounds, including FAAH inhibition, CB1 receptor binding, hERG inhibition, rat plasma PK, and use in pharmaceutical compositions. It also identifies preparation and characterization details for multiple examples and intermediates, and links the compounds to treatment or prevention across a broad set of disease and symptom categories.
Claims Coverage
The claim coverage centers on one inventive feature: a compound selected from Table 1, or a pharmaceutically acceptable salt thereof. Dependent claims extend to pharmaceutical compositions containing a pharmaceutically acceptable carrier, vehicle, or adjuvant, and further to compositions including at least one additional therapeutic agent selected from an enumerated group of drug classes and target categories.
Table 1 compound selection
A compound selected from Table 1.
Pharmaceutically acceptable salt forms
A pharmaceutically acceptable salt thereof.
Pharmaceutical composition with carrier, vehicle, or adjuvant
A pharmaceutical composition including the compound selection and a pharmaceutically acceptable carrier, vehicle, or adjuvant.
Pharmaceutical composition with at least one further therapeutic agent
A pharmaceutical composition including the compound selection and carrier/vehicle/adjuvant, together with at least one further therapeutic agent.
Further therapeutic agent selected from specified drug classes and target categories
The further therapeutic agent is chosen from an enumerated group including analgesics and anti-inflammatories, CNS and psychiatric drugs, cardiovascular and endocrine agents, anti-infectives, GI and respiratory targets, and multiple receptor- or enzyme-targeted categories.
Overall, the claims are directed to Table 1 compounds and pharmaceutically acceptable salts, with dependent pharmaceutical composition embodiments that include formulation components and optionally at least one further therapeutic agent selected from a listed set of drug classes and target categories.
Stated Advantages
Useful for treating or lessening severity of pain.
Useful for treating or lessening severity of inflammation.
Useful for treating or lessening severity of progressive central nervous system diseases.
Useful for treating or lessening severity of neurological diseases.
Useful for treating or lessening severity of autoimmune diseases.
Stated to be usable in combination therapy.
Decreased CB1 receptor binding affinity.
Decreased hERG inhibition.
Increased plasma exposure.
Elevates anandamide (AEA) and other fatty acid amides to increase cannabinoid signaling.
Provides analgesic effects.
Potential utility across pain, depression/anxiety/eating disorders, inflammation, excitotoxic insult, brain trauma, fibromyalgia, multiple sclerosis, and glaucoma.
Documented Applications
Treating or lessening severity of pain.
Treating or lessening severity of inflammation.
Treating or lessening severity of progressive central nervous system diseases.
Treating or lessening severity of neurological diseases.
Treating or lessening severity of autoimmune diseases.
Combination therapy use.
Treatment or prevention for gastrointestinal diseases/disorders.
Treatment or prevention for pruritus.
Treatment or prevention for substance abuse withdrawal-related syndromes.
Treatment or prevention for psychiatric disorders.
Treatment or prevention for neurological/neurodegenerative disorders.
Treatment or prevention for ocular disorders.
Treatment or prevention for appetite-related disorders.
Treatment or prevention for gynecological disorders.
Treatment or prevention for urinary system disorders.
Treatment or prevention for sleep disorders.
Therapeutic context as FAAH inhibitors affecting endogenous cannabinoid (eCB) concentration.
FAAH inhibitor evaluation, including rat and human brain homogenate FAAH IC50 assays and whole-cell anandamide hydrolysis assays.
CB1 receptor radioligand binding assays for assessment of CB1 receptor interaction.
Safety- and pharmacokinetic-related characterization, including hERG inhibition and rat plasma PK.
Analgesia/pain via cannabinoid signaling changes attributed to FAAH inhibition.
Depression, anxiety, and eating disorders via modulation of the endocannabinoid system.
Inflammation via FAAH inhibition and related pathway effects.
Excitotoxic insult via FAAH inhibition and related cannabinoid signaling effects.
Brain trauma via FAAH inhibition and related cannabinoid signaling effects.
Fibromyalgia via FAAH inhibition and related cannabinoid signaling effects.
Multiple sclerosis for symptom relief and disease modification.
Glaucoma with discussion of prostamide/COX-2 pathway involvement.
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