Structural Analogs of the GABAkine KRM-II-81 Are Orally Bioavailable Anticonvulsants without Sedation

Pandey, Kamal Prakash; Divović, Branka; Rashid, Farjana; Golani, Lalit K.; Cerne, Rok; Zahn, Nicolas M; Meyer, Melissa A.; Arnold, Leggy A.; Sharmin, Dishary; Mian, Yeunus; Smith, Jodi L.; Ping, Xingjie; Jin, Xiaoming; Lippa, Arnold S.; Tiruveedhula, V. V. N. Phani Babu; Cook, James M.; Savić, Miroslav M.; Witkin, Jeffrey M.

doi:10.1124/jpet.122.001362

Cited by 4 publications

(14 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The concentrations of compound 5 achieved in these two biological compartments were comparable to those produced by KRM-II-81. , In contrast, other structural analogues of KRM-II-81, compounds 2 and 4 , exhibited lower oral exposures. Substituting a bromine atom (compound 3 ) for the ethynyl of compound 4 helped to reinstate the reductions in plasma and brain exposure . The synthesis of compound 5 was envisioned since it was hypothesized that it would, like 3 , have good oral exposure and, at the same time, produce low levels of motor impairment as noted with 3 .…”

Section: Discussionmentioning

confidence: 99%

“…Substituting a bromine atom (compound 3 ) for the ethynyl of compound 4 helped to reinstate the reductions in plasma and brain exposure . The synthesis of compound 5 was envisioned since it was hypothesized that it would, like 3 , have good oral exposure and, at the same time, produce low levels of motor impairment as noted with 3 . At 2 mg/kg, po, concentrations of compound 5 in both plasma and brain exceeded the K i values for binding to both primary GABAAR target and to the few ancillary targets identified (Table ).…”

Section: Discussionmentioning

confidence: 99%

“…Cultured human embryonic kidney HEK293T cells were used as described . After an 18 h incubation, cell levels were assayed.…”

Section: Methodsmentioning

confidence: 99%

“…Likewise, compound 4 showed a reduced capacity to expose the brain and plasma after oral administration. The bromine analogue of 4 , compound 3 , exhibited the highest areas under the curve for compound concentrations in these compartments upon oral dosing . Two additional features of compound 3 were delineated: (1) very good antiseizure activity with oral dosing across a range of rodent models and (2) the bromine atom of 3 showed the least interaction with α1His102 in molecular docking studies with the α1β3γ2L configured GABAAR, an observation associated with its low sedating activity.…”

Section: Introductionmentioning

confidence: 99%

“…Our goals in achieving a first step toward a backup compound for 1 in development were 3-fold: (1) retain the high level of plasma and brain exposures of the compound after oral dosing; (2) provide initial evidence of anticonvulsant activity; and (3) provide a backup compound with a more efficient synthetic route than compound 1 . The first goal was critical as we had previously shown that some imidazodiazepine analogues of 1 exhibited markedly reduced oral exposures …”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy

Sharmin,

Divović,

Ping

et al. 2024

ACS Chem. Neurosci.

Self Cite

View full text Add to dashboard Cite

KRM-II-81 ( 1) is an imidazodiazepine GABA A receptor (GABAAR) potentiator with broad antiseizure efficacy and a low sedative burden. A brominated analogue, DS-II-73 (5), was synthesized and pharmacologically characterized as a potential backup compound as KRM-II-81 moves forward into development. The synthesis from 2-amino-5-bromophenyl)(pyridin-2yl)methanone (6) was processed in five steps with an overall yield of 38% and without the need for a palladium catalyst. GABAAR binding occurred with a K i of 150 nM, and only 3 of 41 screened binding sites produced inhibition ≥50% at 10 μM, and the potency to induce cytotoxicity was ≥240 mM. DS-II-73 was selective for α2/3/5over that of α1-containing GABAARs. Oral exposure of plasma and brain of rats was more than sufficient to functionally impact GABAARs. Tonic convulsions in mice and lethality induced by pentylenetetrazol were suppressed by DS-II-73 after oral administration and latencies to clonic and tonic seizures were prolonged. Cortical slice preparations from a patient with pharmacoresistant epilepsy (mesial temporal lobe) showed decreases in the frequency of local field potentials by DS-II-73. As with KRM-II-81, the motor-impairing effects of DS-II-73 were low compared to diazepam. Molecular docking studies of DS-II-73 with the α1β3γ2Lconfigured GABAAR showed low interaction with α1His102 that is suggested as a potential molecular mechanism for its low sedative side effects. These findings support the viability of DS-II-73 as a backup molecule for its ethynyl analogue, KRM-II-81, with the human tissue data providing translational credibility.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Cultured human embryonic kidney HEK293T cells were used as described . After an 18 h incubation, cell levels were assayed.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy

Sharmin,

Divović,

Ping

et al. 2024

ACS Chem. Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

The Suppressive Effect of Novel Hydrazones‐Tethered Imidazoles in HCT‐116 and HT‐29 Colorectal Cancer Cells: Synthesis, Biological Activity and Molecular Modeling Studies

Kekeçmuhammed,

Tapera,

Şahin

et al. 2024

ChemistrySelect

View full text Add to dashboard Cite

A series of hybrid compounds containing both the imidazole ring and the hydrazone moiety have been synthesized. Synthesized compounds were characterized by various spectral techniques, including FT‐IR, 1H‐NMR, 13C‐NMR, and HRMS. The compounds were evaluated for their antiproliferative activities on colorectal cancer cells HCT‐116 and HT‐29 in a time‐dependent manner. Among them, some compounds exhibited remarkable anti‐cancer activity with a less cytotoxic effect on non‐cancerous cell lines, especially HRK‐2 with IC50 value of 1.35±0.18 μM in HCT‐116 cells and HRK‐5 with IC50 value of 2.67±0.61 μM in HT‐29 cells. Investigations of colon cancer cell death were performed, and the most active compounds were found to trigger cell death via nuclear localization and induce S phase arrest of the colon cancer cell. Moreover, molecular modeling studies for the synthesized compounds was performed to predict their binding affinities toward the active site of BCL‐2. The findings of the molecular modeling investigations were highly consistent with those of the cytotoxicity results.

show abstract

New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development

Perucca,

White,

Bialer

2023

CNS Drugs

View full text Add to dashboard Cite

The inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays an important role in the modulation of neuronal excitability, and a disruption of GABAergic transmission contributes to the pathogenesis of some seizure disorders. Although many currently available antiseizure medications do act at least in part by potentiating GABAergic transmission, there is an opportunity for further research aimed at developing more innovative GABA-targeting therapies. The present article summarises available evidence on a number of such treatments in clinical development. These can be broadly divided into three groups. The first group consists of positive allosteric modulators of GABA A receptors and includes Staccato ® alprazolam (an already marketed benzodiazepine being repurposed in epilepsy as a potential rescue inhalation treatment for prolonged and repetitive seizures), the α2/3/5 subtype-selective agents darigabat and ENX-101, and the orally active neurosteroids ETX155 and LPCN 2101. A second group comprises two drugs already marketed for non-neurological indications, which could be repurposed as treatments for seizure disorders. These include bumetanide, a diuretic agent that has undergone clinical trials in phenobarbital-resistant neonatal seizures and for which the rationale for further development in this indication is under debate, and ivermectin, an antiparasitic drug currently investigated in a randomised double-blind trial in focal epilepsy. The last group comprises a series of highly innovative therapies, namely GABAergic interneurons (NRTX-001) delivered via stereotactic cerebral implantation as a treatment for mesial temporal lobe epilepsy, an antisense oligonucleotide (STK-001) aimed at upregulating NaV1.1 currents and restoring the function of GABAergic interneurons, currently tested in a trial in patients with Dravet syndrome, and an adenoviral vector-based gene therapy (ETX-101) scheduled for investigation in Dravet syndrome. Another agent, a subcutaneously administered neuroactive peptide (NRP2945) that reportedly upregulates the expression of GABA A receptor α and β subunits is being investigated, with Lennox-Gastaut syndrome and other epilepsies as proposed indications. The diversity of the current pipeline underscores a strong interest in the GABA system as a target for new treatment development in epilepsy. To date, limited clinical data are available for these investigational treatments and further studies are required to assess their potential value in addressing unmet needs in epilepsy management.

show abstract

Structural Analogs of the GABAkine KRM-II-81 Are Orally Bioavailable Anticonvulsants without Sedation

Abstract: diazepin-3yl)oxazole GABAAR -GABA A receptor hERG -human Ether a-go-go related gene = KCNH2 KPP-III-34: 2-(8-bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5α][1,4]diazepin-3yl)-4-ethyloxazole This article has not been copyedited and formatted. The final version may differ from this version.

Cited by 4 publications

References 45 publications

The Suppressive Effect of Novel Hydrazones‐Tethered Imidazoles in HCT‐116 and HT‐29 Colorectal Cancer Cells: Synthesis, Biological Activity and Molecular Modeling Studies

New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development

Contact Info

Product

Resources

About