Browsing by Subject "KRM-II-81"

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    GABAkines – Advances in the Discovery, Development, and Commercialization of Positive Allosteric Modulators of GABAA Receptors
    (Elsevier, 2022) Cerne, Rok; Lippa, Arnold; Poe, Michael M.; Smith, Jodi L.; Jin, Xiaoming; Ping, Xingjie; Golani, Lalit K.; Cook, James M.; Witkin, Jeffrey M.; Anatomy, Cell Biology and Physiology, School of Medicine
    Positive allosteric modulators of γ-aminobutyric acid-A (GABAA) receptors or GABAkines have been widely used medicines for over 70 years for anxiety, epilepsy, sleep, and other disorders. Traditional GABAkines like diazepam have safety and tolerability concerns that include sedation, motor-impairment, respiratory depression, tolerance and dependence. Multiple GABAkines have entered clinical development but the issue of side-effects has not been fully solved. The present review focuses on the new GABAkines in. The compounds that are presently being developed and commercialized include several neuroactive steroids (an allopregnanolone formulation (brexanolone), an allopregnanolone prodrug (LYT-300), Sage-324, zuranolone, and ganaxolone), the α2/3-preferring GABAkine, KRM-II-81, and the α2/3/5-preferring GABAkine PF-06372865 (darigabat). The neuroactive steroids are in clinical development for post-partum depression, intractable epilepsy, tremor, status epilepticus, and genetic epilepsy disorders. Darigabat is in development for epilepsy and anxiety. The imidazodiazepine, KRM-II-81 is efficacious in animal models for the treatment of epilepsy and post-traumatic epilepsy, acute and chronic pain, as well as anxiety and depression. The efficacy of KRM-II-81 in models of pharmacoresistant epilepsy, preventing the development of seizure sensitization, and in brain tissue of intractable epileptic patients bodes well for improved therapeutics. Medicinal chemistry efforts are also ongoing to identify novel and improved GABAkines. The data document gaps in our understanding of the molecular pharmacology of GABAkines that drive differential pharmacological profiles, but emphasize advancements in the ability to successfully utilize GABAA receptor potentiation for therapeutic gain in neurology and psychiatry.
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    Imidazodiazepine Anticonvulsant, KRM-II-81, Produces Novel, Non-diazepam-like Antiseizure Effects
    (ACS, 2020-09) Knutson, Daniel E.; Smith, Jodi L.; Ping, Xingjie; Jin, Xiaoming; Golani, Lalit K.; Li, Guanguan; Tiruveedhula, Vera Venkata Naga Phani Babu; Rashid, Farjana; Mian, Md Yeunus; Jahan, Rajwana; Sharmin, Dishary; Cerne, Rok; Cook, James M.; Witkin, Jeffrey M.; Anatomy and Cell Biology, School of Medicine
    The need for improved medications for the treatment of epilepsy and chronic pain is essential. Epileptic patients typically take multiple antiseizure drugs without complete seizure freedom, and chronic pain is not fully managed with current medications. A positive allosteric modulator (PAM) of α2/3-containing GABAA receptors (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81 (8) is a lead compound in a series of imidazodiazepines. We previously reported that KRM-II-81 produces broad-based anticonvulsant and antinociceptive efficacy in rodent models and provides a wider margin over motoric side effects than that of other GABAA receptor PAMs. The present series of experiments was designed to fill key missing gaps in prior preclinical studies assessing whether KRM-II-81 could be further differentiated from nonselective GABAA receptor PAMs using the anticonvulsant diazepam (DZP) as a comparator. In multiple chemical seizure provocation models in mice, KRM-II-81 was either equally or more efficacious than DZP. Most strikingly, KRM-II-81 but not DZP blocked the development of seizure sensitivity to the chemoconvulsants cocaine and pentylenetetrazol in seizure kindling models. These and predecessor data have placed KRM-II-81 into consideration for clinical development requiring the manufacture of kilogram amounts of good manufacturing practice material. We describe here a novel synthetic route amenable to kilogram quantity production. The new biological and chemical data provide key steps forward in the development of KRM-II-81 (8) as an improved treatment option for patients suffering from epilepsy.