ABSTRACT
RIP1 regulates cell death and inflammation and is believed to play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases and cancer. While small-molecule inhibitors of RIP1 kinase have been advanced to the clinic for inflammatory diseases and CNS indications, RIP1 inhibitors for oncology indications have yet to be described. Herein we report on the discovery and profile of GSK3145095 (compound 6). Compound 6 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking RIP1 kinase-dependent cellular responses. Highlighting its potential as a novel cancer therapy, the inhibitor was also able to promote a tumor suppressive T cell phenotype in pancreatic adenocarcinoma organ cultures. Compound 6 is currently in phase 1 clinical studies for pancreatic adenocarcinoma and other selected solid tumors.
ABSTRACT
RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Nuclear Pore Complex Proteins/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , RNA-Binding Proteins/antagonists & inhibitors , Animals , Biological Availability , Cell Line , Chronic Disease , Drug Design , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Enzyme Inhibitors/pharmacokinetics , Haplorhini , High-Throughput Screening Assays , Humans , Mice , Mice, Inbred C57BL , Models, Molecular , Multiple Sclerosis/drug therapy , Pyrazoles/pharmacokinetics , Rats , Retinitis Pigmentosa/drug therapy , Structure-Activity RelationshipABSTRACT
RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compound 5 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous production of cytokines from human ulcerative colitis explants. The highly favorable physicochemical and ADMET properties of 5, combined with high potency, led to a predicted low oral dose in humans.
Subject(s)
Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Colitis, Ulcerative/drug therapy , Inflammation/drug therapy , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Receptor-Interacting Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Benzazepines/chemistry , Benzazepines/pharmacology , Colitis, Ulcerative/immunology , Cytokines/immunology , Dogs , Haplorhini , Humans , Inflammation/immunology , Mice , Molecular Docking Simulation , Rabbits , Rats , Receptor-Interacting Protein Serine-Threonine Kinases/immunology , Swine , Swine, Miniature , Tumor Necrosis Factor-alpha/immunologyABSTRACT
We describe the structure-activity relationship of the C1-group of pyrano[3,4-b]indole based inhibitors of HCV NS5B polymerase. Further exploration of the allosteric binding site led to the discovery of the significantly more potent compound 12.
Subject(s)
Antiviral Agents/chemistry , Enzyme Inhibitors/chemistry , Indoles/chemistry , Pyrans/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Binding Sites , Crystallography, X-Ray , Drug Discovery , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Pyrans/chemical synthesis , Pyrans/pharmacology , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolismABSTRACT
A lead optimization campaign in our previously reported sulfamoyl benzamide class of CB(2) agonists was conducted to improve the in vitro metabolic stability profile in this series while retaining high potency and selectivity for the CB(2) receptor. From this study, compound 14, N-(3,4-dimethyl-5-(morpholinosulfonyl)phenyl)-2,2-dimethylbutanamide, was identified as a potent and selective CB(2) agonist exhibiting moderate in vitro metabolic stability and oral bioavailability. Compound 14 demonstrated in vivo efficacy in a rat model of post-surgical pain.
Subject(s)
Aniline Compounds/chemistry , Benzamides/chemistry , Receptor, Cannabinoid, CB2/agonists , Sulfonamides/chemistry , Aniline Compounds/chemical synthesis , Aniline Compounds/pharmacokinetics , Animals , Benzamides/chemical synthesis , Benzamides/pharmacokinetics , Humans , Microsomes, Liver/metabolism , Pain/drug therapy , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokineticsABSTRACT
A series of imidazopyrimidine derivatives with the general formula I was synthesized and identified as potent inhibitors of iNOS dimer formation, a prerequisite for proper functioning of the enzyme. Stille and Negishi coupling reactions were used as key steps to form the carbon-carbon bond connecting the imidazopyrimidine core to the central cycloalkenyl, cycloalkyl and phenyl ring templates.
ABSTRACT
Selective, nonpeptidic delta opioid receptor agonists have been the subject of great interest as potential novel analgesic agents. The discoveries of BW373U86 (1) and SNC80 (2) contributed to the rapid expansion of research in this field. However, poor drug-like properties and low therapeutic indices have prevented clinical evaluation of these agents. Doses of 1 and 2 similar to those required for analgesic activity produce convulsions in rodents and nonhuman primates. Recently, we described a novel series of potent, selective, and orally bioavailable delta opioid receptor agonists. The lead derivative, ADL5859 (4), is currently in phase II proof-of-concept studies for the management of pain. Further structure activity relationship exploration has led to the discovery of ADL5747 (36), which is approximately 50-fold more potent than 4 in an animal model of inflammatory pain. On the basis of its favorable efficacy, safety, and pharmacokinetic profile, 36 was selected as a clinical candidate for the treatment of pain.
Subject(s)
Analgesics/pharmacology , Analgesics/therapeutic use , Benzamides/pharmacology , Benzamides/therapeutic use , Benzopyrans/pharmacology , Benzopyrans/therapeutic use , Pain/drug therapy , Receptors, Opioid, delta/agonists , Spiro Compounds/pharmacology , Spiro Compounds/therapeutic use , Analgesics/administration & dosage , Analgesics/chemistry , Animals , Benzamides/administration & dosage , Benzamides/chemistry , Benzopyrans/administration & dosage , Benzopyrans/chemistry , CHO Cells , Clinical Trials as Topic , Cricetinae , Cricetulus , Crystallography, X-Ray , Cytochrome P-450 CYP2D6 Inhibitors , Dogs , Dose-Response Relationship, Drug , Drug Discovery , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Hyperalgesia/drug therapy , Male , Rats , Rats, Sprague-Dawley , Spiro Compounds/administration & dosage , Spiro Compounds/chemistryABSTRACT
Among the various human cytochrome P450s (CYP450s) that catalyze the biotransformation of xenobiotics, CYP450 2D6 (CYP2D6) is one of the most important based on the number and wide variety of its drug substrates. CYP2D6 shows a high degree of interindividual variability, which is primarily due to the extensive genetic polymorphism that influences its expression and function. A number of drugs have been clinically implicated in major drug-drug interactions (DDI) via CYP2D6 inhibition. In order to avoid or minimize issues related to CYP2D6-mediated DDIs, pharmaceutical companies routinely screen for potential CYP2D6 liability of lead candidates in the early stage of the drug discovery process. This review summarizes the medicinal chemistry tactics employed to mitigate inhibitory activity at CYP2D6, identified through an extensive literature survey covering the 1998-2008 period.
Subject(s)
Cytochrome P-450 CYP2D6 Inhibitors , Adrenergic beta-Antagonists/chemistry , Adrenergic beta-Antagonists/pharmacology , Analgesics/chemistry , Analgesics/pharmacology , Anti-Arrhythmia Agents/chemistry , Anti-Arrhythmia Agents/pharmacology , Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacology , Chemistry, Pharmaceutical , Cytochrome P-450 CYP2D6/metabolism , Drug Design , Humans , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolismABSTRACT
Selective delta opioid receptor agonists are promising potential therapeutic agents for the treatment of various types of pain conditions. A spirocyclic derivative was identified as a promising hit through screening. Subsequent lead optimization identified compound 20 (ADL5859) as a potent, selective, and orally bioavailable delta agonist. Compound 20 was selected as a clinical candidate for the treatment of pain.
Subject(s)
Analgesics/administration & dosage , Benzamides/administration & dosage , Benzopyrans/administration & dosage , Pain/drug therapy , Receptors, Opioid, delta/agonists , Administration, Oral , Analgesics/chemical synthesis , Analgesics/chemistry , Animals , Benzamides/chemical synthesis , Benzamides/chemistry , Benzopyrans/chemical synthesis , Benzopyrans/chemistry , Biological Availability , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Drug-Related Side Effects and Adverse Reactions , Ether-A-Go-Go Potassium Channels/drug effects , Humans , Maximum Tolerated Dose , Mice , Molecular Structure , Motor Activity/drug effects , Pain Measurement/drug effects , Rats , Toxicity TestsABSTRACT
Nitric oxide (NO), a mediator of various physiological and pathophysiological processes, is synthesized by three isozymes of nitric oxide synthase (NOS). Potential candidate clinical drugs should be devoid of inhibitory activity against endothelial NOS (eNOS), since eNOS plays an important role in maintaining normal blood pressure and flow. A new series of aminopiperidines as potent inhibitors of iNOS were identified from a HTS lead. From this study, we identified compound 33 as a potent iNOS inhibitor, with >25-fold selectivity over eNOS and 16-fold selectivity over nNOS.
