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Patent
Abide Therapeutics | Date: 2016-09-21

This disclosure provides compounds and compositions which may be modulators of MAGL and/or ABHD6 and their use as medicinal agents, processes for their preparation, and pharmaceutical compositions that include disclosed compounds as at least one active agent. The disclosure also provides for method of treating a patient in need thereof, where the patient is suffering from indications such as pain, solid tumor cancer and/or obesity comprising administering a disclosed compound or composition.


"The ABX-1431 fMRI study provides a long-awaited opportunity to verify whether the mode of action of a CNS-active drug based on brain imaging can be predicted," said Irene Tracey, DPhil., FRCA, FMedSci, Principal Investigator, Head of Department and Nuffield Chair in Anaesthetic Science, Nuffield Department of Clinical Neurosciences, University of Oxford. "Understanding the activity of this compound in the brain has the potential to be a foundational step in the development of CNS-active drugs." In order to evaluate a brain signature of ABX-1431, neural activity in response to induced cutaneous hyperalgesia is assessed by fMRI following a single dose of ABX-1431, and compared to brain activity following placebo and no treatment interventions. Similar fMRI brain imaging studies have been used to identify the functional pharmacological activity of a number of therapies (including the exocannabinoid THC) with proven clinical efficacy in the treatment of pain. "At Abide Therapeutics, we are excited to initiate this fMRI study that will give us new insights into how ABX-1431 may work in the brain," said Alan Ezekowitz, MBChB, DPhil, CEO and President of Abide Therapeutics. "As we continue to explore the potential utility of ABX-1431 for the treatment of neurological disorders, we believe our partnership with the University of Oxford on this study will allow us to better understand the neural basis for the activity of ABX-1431 in the brain and provide insight into the future potential for the compound." ABX-1431 has successfully completed dosing in a first-in-human, placebo-controlled, Phase 1 study. The drug was generally well tolerated, and there were no serious adverse events. Preliminary data from a PET occupancy study indicate dose-dependent brain penetrance of orally-administered ABX-1431 using [18F]ABX-1488, an Abide proprietary, MGLL-specific PET ligand. A study of ABX-1431 in patients with Tourette Syndrome was initiated in early 2017 and is ongoing. Cannabinoid receptor 1 (CB1) is critical to regulating neurotransmission. It is the most highly expressed G-protein coupled receptor in the brain, and its main endogenous ligand is 2-arachidonoylglycerol (2-AG). Monoacylglycerol lipase (MGLL) is an enzyme that catalyzes the breakdown of 2-AG, and as a result regulates the activation of CB1. A second cannabinoid receptor, CB2, which is found primarily on immune cells and is thought to mediate certain immune functions, also has 2-AG as an endogenous ligand. Preclinical studies with MGLL inhibitors demonstrate that raising the level of 2-AG has multiple therapeutic effects, including reduction of pain responses, control of spasticity, anxiolytic effects, and reduction of neurodegenerative pathology. Direct activation of cannabinoid receptors by medicinal cannabis demonstrates therapeutic benefits on pain, spasticity, sleep, appetite, and nausea. Cannabis indiscriminately activates cannabinoid receptors throughout the body; this non-selective activity is likely responsible for the numerous psychoactive side effects of medical cannabis, and limits clinical use. In contrast, inhibiting MGLL enhances 2-AG concentrations locally, which is expected to rectify neurotransmitter balance through activation of presynaptic CB1 receptors. Abide Therapeutics is developing ABX-1431, a first-in-class, small-molecule inhibitor of monoacylglycerol lipase (MGLL) to treat neurological disorders, pain, and neuroinflammation. ABX-1431, a potent and selective inhibitor of MGLL, has been shown to modulate 2-arachidonoylglycerol (2-AG) levels in preclinical species and is expected to produce beneficial effects in humans through selective elevation of 2-AG.  MGLL inhibition causes an elevation of 2-AG in the brain and propagates signaling through the CB1 endocannabinoid receptor pathway. Additionally, MGLL inhibition by ABX-1431 depletes the supply of the inflammatory signaling molecule arachidonic acid, thereby providing another potential mechanism for alleviating pain and inflammation. In September 2016, Celgene exercised its option to obtain ex-US rights to ABX-1431. Celgene will be responsible for development costs for all indications from Phase 2 clinical trials and beyond, while Abide retains US rights and is conducting a number of Phase 1b studies to explore indications where endocannabinoid modulation may affect disease progression. Abide Therapeutics combines an innovative discovery platform and a library of proprietary small molecules to address biological pathways with therapeutics that enhance the body's normal physiological response to disease. The platform enables Abide to quickly and efficiently identify, modify and validate small molecule inhibitors that target serine hydrolases, a highly relevant but under-explored class of enzymes. Abide's initial area of focus is on addressing neurological disorders with limited treatment options through the endocannabinoid pathway. Abide is located in San Diego, California. To learn more, visit www.abidetx.com To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/abide-therapeutics-announces-dosing-of-first-subject-in-fmri-imaging-study-to-investigate-brain-activity-patterns-associated-with-abx-1431-300454350.html


In the study presented at EUFEMED, Abide evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of ABX-1431 in single and multiple ascending doses. The drug was generally well tolerated at doses planned for future studies, with no serious adverse events, and the study data supported further clinical evaluation of this first-in-mechanism MGLL inhibitor in patient populations. A study of ABX-1431 in patients with Tourette Syndrome was initiated in early 2017 and is ongoing. "Abide's scientific tools produced an extensively characterized clinical candidate, generated a translatable clinical biomarker, and greatly facilitated this first clinical evaluation of a MGLL inhibitor," said Iain Fraser, MBChB, DPhil, Head of Early Clinical Development at Abide Therapeutics, and clinical lead for the ABX-1431 first-in-human study. "These clinical data indicate that ABX-1431 modulates CNS activity in a dose-related fashion, and have refined the anticipated ABX-1431 dose range for further clinical evaluation in patient populations." Details of the poster presentations are as follows: Title: Preclinical Characterization and First-in-Human Administration of a Selective Monoacylglycerol Lipase Inhibitor, ABX-1431 Location: Kensington Conference and Events Centre, London Date & Time: Thursday, May 18, 1:15 – 2:00 PM GMT Cannabinoid receptor 1 (CB1) is critical to regulating neurotransmission. It is the most highly expressed G-protein coupled receptor in the brain, and its main endogenous ligand is 2-arachidonoylglycerol (2-AG). Monoacylglycerol lipase (MGLL) is an enzyme that catalyzes the breakdown of 2-AG, and as a result regulates the activation of CB1. A second cannabinoid receptor, CB2, which is found primarily on immune cells and is thought to mediate certain immune functions, also has 2-AG as an endogenous ligand. Preclinical studies with MGLL inhibitors demonstrate that raising the level of 2-AG has multiple therapeutic effects, including reduction of pain responses, control of spasticity, anxiolytic effects, and reduction of neurodegenerative pathology. Direct activation of cannabinoid receptors by medicinal cannabis demonstrates therapeutic benefits on pain, spasticity, sleep, appetite, and nausea. Cannabis indiscriminately activates cannabinoid receptors throughout the body; this non-selective activity is likely responsible for the numerous psychoactive side effects of medical cannabis, and limits clinical use. In contrast, inhibiting MGLL enhances 2-AG concentrations locally, which is expected to rectify neurotransmitter balance through activation of presynaptic CB1 receptors. Abide Therapeutics is developing ABX-1431, a first-in-class, small-molecule inhibitor of monoacylglycerol lipase (MGLL), to treat neurological disorders, pain, and neuroinflammation. ABX-1431, a potent and selective inhibitor of MGLL, has been shown to modulate 2-arachidonoylglycerol (2-AG) levels in preclinical species and is expected to produce beneficial effects in humans through selective elevation of 2-AG.  MGLL inhibition causes an elevation of 2-AG in the brain and propagates signaling through the CB1 endocannabinoid receptor pathway. Additionally, MGLL inhibition by ABX-1431 is believed to deplete the supply of the inflammatory signaling molecule arachidonic acid, thereby providing another potential mechanism for alleviating pain and inflammation. In September 2016, Celgene exercised its option to obtain ex-US rights to ABX-1431. Celgene will be responsible for development costs for all indications from Phase 2 clinical trials and beyond, while Abide retains US rights and is conducting a number of Phase 1b studies to explore indications where endocannabinoid modulation may affect disease progression. Abide Therapeutics combines an innovative discovery platform and a library of proprietary small molecules to address biological pathways with therapeutics that enhance the body's normal physiological response to disease. The platform enables Abide to quickly and efficiently identify, modify and validate small molecule inhibitors that target serine hydrolases, a highly relevant but under-explored class of enzymes. Abide's initial area of focus is on addressing neurological disorders with limited treatment options through the endocannabinoid pathway. Abide is located in San Diego, California. To learn more, visit www.abidetx.com To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/abide-therapeutics-to-present-at-eufemed-annual-meeting-on-abx-1431-clinical-program-300458562.html


Blankman J.L.,Scripps Research Institute | Blankman J.L.,Abide Therapeutics | Cravatt B.F.,Scripps Research Institute
Pharmacological Reviews | Year: 2013

The endocannabinoid signaling system regulates diverse physiologic processes and has attracted considerable attention as a potential pharmaceutical target for treating diseases, such as pain, anxiety/ depression, and metabolic disorders. The principal ligands of the endocannabinoid system are the lipid transmitters N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), which activate the two major cannabinoid receptors, CB1 and CB2. Anandamide and 2-AG signaling pathways in the nervous system are terminated by enzymatic hydrolysis mediated primarily by the serine hydrolases fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. In this review, we will discuss the development of FAAH and MAGL inhibitors and their pharmacological application to investigate the function of anandamide and 2-AG signaling pathways in preclinicalmodels of neurobehavioral processes, such as pain, anxiety, and addiction. We will place emphasis on how these studies are beginning to discern the different roles played by anandamide and 2-AG in the nervous system and the resulting implications for advancing endocannabinoid hydrolase inhibitors as next-generation therapeutics. © 2013 by The American Society for Pharmacology and Experimental Therapeutics.


Patent
Abide Therapeutics and Scripps Research Institute | Date: 2013-01-07

This disclosure provides compounds and compositions which may be modulators of MAGL and/or ABHD6 and their use as medicinal agents, processes for their preparation, and pharmaceutical compositions that include disclosed compounds as at least one active agent. The disclosure also provides for method of treating a patient in need thereof, where the patient is suffering from indications such as pain, solid tumor cancer and/or obesity comprising administering a disclosed compound or composition.


Patent
Abide Therapeutics and Scripps Research Institute | Date: 2013-03-15

Provided herein are carbamate compounds which may be useful in the treatment of for example, pain, solid tumors and/or obesity.


Patent
Abide Therapeutics | Date: 2016-03-16

Provided herein are piperazine carbamates and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful as modulators of MAGL and/or ABHD6. Furthermore, the subject compounds and compositions are useful for the treatment of pain.


The invention provides pyrrolo-pyrrole carbamate and related organic compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat medical disorders, e.g., solid tumor cancer, obesity, Downs syndrome, Alzheimers disease, or pain, in a patient. The octahydropyrrolo pyrrole carbamates could be derived from hexafluoroisopropanol, N,N-disuccinimide and such. The activity of carbamates in MAGL, FAAH, and ABHD6 assays are also described.


Patent
Abide Therapeutics and Scripps Research Institute | Date: 2015-01-16

This disclosure provides compounds and compositions which may be modulators of MAGL and/or ABHD6 and their use as medicinal agents, processes for their preparation, and pharmaceutical compositions that include disclosed compounds as at least one active agent. The disclosure also provides for method of treating a patient in need thereof, where the patient is suffering from indications such as pain, solid tumor cancer and/or obesity comprising administering a disclosed compound or composition.


SAN DIEGO, Dec. 14, 2016 /PRNewswire/ -- Abide Therapeutics, a developer of innovative pharmaceuticals, announced today initiation of dosing in a Phase 1b study to evaluate the effects of ABX-1431, a first-in-class investigational monoacylglycerol lipase (MGLL) inhibitor, on gastric...

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