Imidazodiazepine Anticonvulsant, KRM-II-81, Produces Novel, Non-diazepam-like Antiseizure Effects

Knutson, Daniel E; Smith, Jodi L.; Ping, Xingjie; Jin, Xiaoming; Golani, Lalit K.; Li, Guanguan; Tiruveedhula, V. V. N. Phani Babu; Rashid, Farjana; Mian, Yeunus; Jahan, Rajwana; Sharmin, Dishary; Cerne, Rok; Cook, James M.; Witkin, Jeffrey M.

doi:10.1021/acschemneuro.0c00295

Cited by 12 publications

(27 citation statements)

References 52 publications

(149 reference statements)

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“…The CHIRALPAK ® IB-N3 HPLC Column from Daicel Corporation was used for confirmation of enantiomeric excess. The 1 H and 13 C NMR spectra were obtained on Bruker Spectrospin 500 MHz or 300 MHz instruments in CDCl 3 and chemical shifts were reported in δ (ppm). Multiplicities are represented as follows: singlet (s), broad signal (br), doublet (d), triplet (t), quartet (q), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets) and multiplet (m).…”

Section: Methodsmentioning

confidence: 99%

“…Recently our research group published an improved large-scale synthesis of the ethyl ester 1. 13 The ester 1 was then heated to 90 °C with substituted ethanolamines (individually) in a sealed tube to afford -hydroxy amides 2a-2d that were purified by chromatography and in 80-98% yield. The -hydroxy amides 2, 2a and 2c were then oxidized by treatment with the Dess-Martin reagent to provide the corresponding acylaminoaldehydes 3, 3a and 3c, which were purified by crystallization, in 75-81% yield (Scheme 1).…”

Section: Chemistrymentioning

confidence: 99%

“…1 H NMR (500 MHz, CDCl 3 ): δ H 9.67 (s, 1H), 8.57 (ddd, J 4.8, 1.8, 0.9 Hz, 1H), 8.15 (dt, J 7.9, 1.1 Hz, 1H), 7.87 -7.80 (m, 2H), 7.78 (dd, J 8.6, 2.2 Hz, 1H), 7.61 (t, J 4.5 Hz, 2H), 7.45 (d, J 8.5 Hz, 1H), 7.37 (ddd, J 7.6, 4.8, 1.2 Hz, 1H), 6.25 (d, J 12.5 Hz, 1H), 4.63 (m, 1H), 4.14 (d, J 12.7 Hz, 1H)), 1.46 (d, J 7.4 Hz, 3H). 13…”

Section: (S)-8-bromo-n-(1-oxopropan-2-yl)-6-(pyridin-2-yl)-4h-benzo[f...mentioning

confidence: 99%

“…1 H NMR (500 MHz, CDCl 3 ): δ H 8.57 (q, J 2.7 Hz, 1H), 8.08 (d, J 6.9 Hz, 1H), 7.95 (s, 1H), 7.82 (d, J 2.4 Hz, 1H), 7.79 (q, J 1.8 Hz, 1H), 7.77 (p, J 2.3 Hz, 1H), 7.72 -7.65 (m, 1H), 7.57 (d, J 2.1 Hz, 1H), 7.50 (d, J 8.5 Hz, 1H), 7.36 (ddt, J 7.3, 4.9, 1.2 Hz, 2H), 6.14 (d, J 12.7 Hz, 1H), 4.27 (d, J 12.7 Hz, 1H), 2.25 (d, J 1.3 Hz, 3H). 13 C NMR (126 MHz, CDCl 3 ): δ C δ 167.1 (s), 162.7 (s), 156.8 (s), 156.4 (s), 148.7 (s), 137.4 (s), 136.9 (s), 136.2 (s), 135.4 (s), 134.9 (s), 134.6 (s), 133.5 (s), 130.9 (s), 128.5 (s), 124.8 (s), 124.2 (s), 124.0 (s), 120. 4c).…”

Section: -(8-bromo-6-(pyridin-2-yl)-4h-benzo[f]imidazo[15-a][14]diaze...mentioning

confidence: 99%

“…1 25 (d, J 13.1 Hz, 1H), 2.62 (q, J 7.5 Hz, 2H), 1.27 (t, J 7.5 Hz, 3H). 13 C NMR (126 MHz, CDCl 3 ): δ C 167.5 (s), 157.0 (s), 156.7 (s), 149.0 (s), 144.1 (s), 137.3 (s), 135.7 (s), 135.4 (s), 135.3 (s), 135.2 (s), 133.2 (s), 133.1 (s), 128.9 (s), 128.0 (s), 125.3 (s), 124.6 (s), 124.4 (s), 120.7 (s), 45.4 (s), 20.3 (s), 13.0 (s). HRMS (ESI/IT-TOF) m/z: [M + H] + Calcd for C 21 H 16 N 5 OBr 434.0616; found 434.0596.…”

Section: -(8-bromo-6-(pyridin-2-yl)-4h-benzo[f]imidazo[15-a][14]diaze...mentioning

confidence: 99%

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Design, synthesis and characterization of novel gamma‑aminobutyric acid type A receptor ligands

Pandey¹,

Khan²,

Golani³

et al. 2020

Arkivoc

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Section: Methodsmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: (S)-8-bromo-n-(1-oxopropan-2-yl)-6-(pyridin-2-yl)-4h-benzo[f...mentioning

confidence: 99%

Section: -(8-bromo-6-(pyridin-2-yl)-4h-benzo[f]imidazo[15-a][14]diaze...mentioning

confidence: 99%

Section: -(8-bromo-6-(pyridin-2-yl)-4h-benzo[f]imidazo[15-a][14]diaze...mentioning

confidence: 99%

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Design, synthesis and characterization of novel gamma‑aminobutyric acid type A receptor ligands

Pandey¹,

Khan²,

Golani³

et al. 2020

Arkivoc

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New and Emerging Antiepileptic Drugs

Witkin

Golani

Smith

2021

Burger's Medicinal Chemistry and Drug Discovery

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This article provides the biologist, chemist, and clinician with an overview into currently existing epilepsy medicines, an appreciation of those currently in development, and a glimpse at future possibilities. The discovery and development of antiepileptic drugs with improved efficacy and side‐effect dimensions are urgently needed. We discuss various strategies for discovering new antiepileptic drugs. We then provide summary data on the mechanisms of action, efficacy, and tolerability of some of the newer third‐generation antiepileptic drugs – eslicarbazepine, brivaracetam, retigabine, lacosamide, and perampanel. Additional compounds that are currently in development for epilepsy are also reviewed. These include the novel α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor antagonists CERC‐611 and JNJ‐55511118 that are first‐in‐class drugs blocking only those AMPA receptors associated with the auxiliary protein TAPP γ‐8. The GABA A (α2/3)‐selective compounds, KRM‐II‐81, MP‐III‐080, and PF‐06372865 hold additional promise and potential advantage over nonselective GABA A receptor modulators. The developmental status of another positive allosteric modulator of GABA A receptors, the neuroactive steroid ganaxolone, is also summarized. In addition, two mGlu2 receptor modulators, JNJ‐40411813 and LY2812223 are discussed. Finally, initial data on cannabidiol, anakinra, and padsevonil are reviewed. Literature data derived from studies on both human epileptic tissue and rodent seizure modeling were utilized to glean several compelling novel drug targets for consideration in future antiepileptic drug discovery programs. Thus, in the past decade, key advances have been made that are benefiting the epileptic patient community. The current compounds in development and new drug targets give additional promise of improved antiepileptic drugs.

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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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Imidazodiazepine Anticonvulsant, KRM-II-81, Produces Novel, Non-diazepam-like Antiseizure Effects

Abstract: pharmacology and biology, outstanding contributions to the field of neuroscience, drug development, and the treatment of drug abuse. In gratitude for 40 years of fruitful collegial interaction and advancements with our friend.

Cited by 12 publications

References 52 publications

Design, synthesis and characterization of novel gamma‑aminobutyric acid type A receptor ligands

Design, synthesis and characterization of novel gamma‑aminobutyric acid type A receptor ligands

New and Emerging Antiepileptic Drugs

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

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