GABAkines – Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors

Cerne, Rok; Lippa, Arnold S.; Poe, M.; Smith, Jodi L.; Jin, Xiaoming; Ping, Xingjie; Golani, Lalit K.; Cook, James M.; Witkin, Jeffrey M.

doi:10.1016/j.pharmthera.2021.108035

Cited by 53 publications

(57 citation statements)

References 387 publications

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“…KRM‐II‐81, one of the most recent GABAkines to be considered for clinical development (Cerne et al., 2021; Witkin et al, 2022), was rationally designed to overcome the metabolic liabilities of the predecessor imidazodiazepine GABAkine, HZ‐166. KRM‐II‐81 is an oxazole bioisostere of HZ‐166 with the oxazole replacing the metabolically‐vulnerable ester function of HZ‐166 (Poe et al., 2016).…”

Section: Discussionmentioning

confidence: 99%

“…KRM‐II‐81 (5‐(8‐ethynyl‐6‐(pyridin‐2‐yl)‐4H‐benzo [ f ]imidazole[1,5‐α][1,4]diazepin‐3‐yl) oxazole) is a new GABAkine (gamma aminobutyric acid A [GABA A ] receptor potentiator) with anticonvulsant, anxiolytic, and antinociceptive activity in preclinical models (Biggerstaff et al., 2020; Cerne et al., 2019; Knutson et al., 2020; Lewter et al., 2017; Poe et al., 2016; Witkin et al., 2017, 2018, 2019, 2020, 2022). This imidazodiazepine, is one of several new GABAkines that have recently been targeted for clinical investigation (Cerne et al., 2021). KRM‐II‐81 is currently under preparation for clinical development (RespireRx Pharmaceuticals Inc).…”

Section: Introductionmentioning

confidence: 99%

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Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3‐selective GABAkine KRM‐II‐81

Golani

Divović

Sharmin

et al. 2022

Biopharm & Drug Disp

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The imidazodiazepine, (5‐(8‐ethynyl‐6‐(pyridin‐2‐yl)‐4H‐benzo [f]imidazole[1,5‐α][1,4]diazepin‐3‐yl) oxazole or KRM‐II‐81) is a new α2/3‐selective GABAkine (gamma aminobutyric acid A receptor potentiator) with anticonvulsant, anxiolytic, and antinociceptive activity in preclinical models. Reducing metabolism was utilized as a means of potentially extending the half‐life of KRM‐II‐81. In vitro and in vivo studies were conducted to evaluate metabolic liabilities. Incubation of KRM‐II‐81 in hepatocytes revealed sites of potential metabolism on the oxazole and the diazepine rings. These sites were targeted in the design of a deuterated analog (D5‐KRM‐II‐81) that could be evaluated as a potentially longer‐acting analog. In contrast to computer predictions, peak plasma concentrations of D5‐KRM‐II‐81 in rats were not significantly greater than those produced by KRM‐II‐81 after oral administration. Furthermore, brain disposition of KRM‐II‐81 was higher than that of D5‐KRM‐II‐81. The half‐life of the two compounds in either plasma or brain did not statistically differ from one another but the tmax for D5‐KRM‐II‐81 occurred slightly earlier than for KRM‐II‐81. Non‐metabolic considerations might be relevant to the lack of increases in exposure by D5‐KRM‐II‐81. Alternative sites of metabolism on KRM‐II‐81, not targeted by the current deuteration process, are also possible. Despite its lack of augmented exposure, D5‐KRM‐II‐81, like KRM‐II‐81, significantly prevented seizures induced by pentylenetetrazol when given orally. The present findings introduce a new orally active anticonvulsant GABAkine, D5‐KRM‐II‐81.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3‐selective GABAkine KRM‐II‐81

Golani

Divović

Sharmin

et al. 2022

Biopharm & Drug Disp

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“…One publication reported decreased activity for diazepam in a similar concentration range as the present study, and the other paper reported behavioral changes, but whether it was an increase or decrease in activity was unclear as only a lowest effective dose was reported. As diazepam is known to be pharmacologically active at the gamma-aminobutyric acid receptor (reviewed in [ 91 ]), perhaps diazepam could be regarded as a positive control for GABAergic chemicals. For fluoxetine, one publication, as well as our own, reported decreased activity in larvae treated with fluoxetine during development, while another publication reported increased activity in animals treated with fluoxetine transiently during an early developmental window.…”

Section: Discussionmentioning

confidence: 99%

Developmental Neurotoxicity and Behavioral Screening in Larval Zebrafish with a Comparison to Other Published Results

Jarema

Hunter

Hill

et al. 2022

Toxics

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With the abundance of chemicals in the environment that could potentially cause neurodevelopmental deficits, there is a need for rapid testing and chemical screening assays. This study evaluated the developmental toxicity and behavioral effects of 61 chemicals in zebrafish (Danio rerio) larvae using a behavioral Light/Dark assay. Larvae (n = 16–24 per concentration) were exposed to each chemical (0.0001–120 μM) during development and locomotor activity was assessed. Approximately half of the chemicals (n = 30) did not show any gross developmental toxicity (i.e., mortality, dysmorphology or non-hatching) at the highest concentration tested. Twelve of the 31 chemicals that did elicit developmental toxicity were toxic at the highest concentration only, and thirteen chemicals were developmentally toxic at concentrations of 10 µM or lower. Eleven chemicals caused behavioral effects; four chemicals (6-aminonicotinamide, cyclophosphamide, paraquat, phenobarbital) altered behavior in the absence of developmental toxicity. In addition to screening a library of chemicals for developmental neurotoxicity, we also compared our findings with previously published results for those chemicals. Our comparison revealed a general lack of standardized reporting of experimental details, and it also helped identify some chemicals that appear to be consistent positives and negatives across multiple laboratories.

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“…KRM-II-81 is the latest in a series of imidazodiazepine potentiators of GABA A receptors (GABAARs) or GABAkines that is under development. 1 , 2 KRM-II-81 produces anxiolytic effects, 3 , 4 antidepressant-like activity, 5 anticonvulsant activity, 6 − 9 and efficacy in a host of acute and chronic pain models in rodents. 10 The efficacy of KRM-II-81 is associated with a low sedative and motor-impairing profile, lack of tolerance development, and abuse liability.…”

Section: Introductionmentioning

confidence: 99%

Hydrochloride Salt of the GABAkine KRM-II-81

et al. 2022

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Imidazodiazepine (5-(8-ethynyl-6-(pyridin-2-yl)-4 H -benzo[ f ]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81) is a potentiator of GABA A receptors (a GABAkine) undergoing preparation for clinical development. KRM-II-81 is active against many seizure and pain models in rodents, where it exhibits improved pharmacological properties over standard-of-care agents. Since salts can be utilized to create opportunities for increased solubility, enhanced absorption, and distribution, as well as for efficient methods of bulk synthesis, a hydrochloride salt of KRM-II-81 was prepared. KRM-II-81·HCl was produced from the free base with anhydrous hydrochloric acid. The formation of the monohydrochloride salt was confirmed by X-ray crystallography, as well as 1 H NMR and 13 C NMR analyses. High water solubility and a lower partition coefficient (octanol/water) were exhibited by KRM-II-81·HCl as compared to the free base. Oral administration of either KRM-II-81·HCl or the free base resulted in high concentrations in the brain and plasma of rats. Oral dosing in mice significantly increased the latency to both clonic and tonic convulsions and decreased pentylenetetrazol-induced lethality. The increased water solubility of the HCl salt enables intravenous dosing and the potential for higher concentration formulations compared with the free base without impacting anticonvulsant potency. Thus, KRM-II-81·HCl adds an important new compound to facilitate the development of these imidazodiazepines for clinical evaluation.

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GABAkines – Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors

Cited by 53 publications

References 387 publications

Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3‐selective GABAkine KRM‐II‐81

Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3‐selective GABAkine KRM‐II‐81

Developmental Neurotoxicity and Behavioral Screening in Larval Zebrafish with a Comparison to Other Published Results

Hydrochloride Salt of the GABAkine KRM-II-81

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