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

Pandey, Kamal Prakash; Khan, Zakaullah; Golani, Lalit K.; Mondal, Prithu; Mian, Yeunus; Rashid, Farjana; Tiruveedhula, V. V. N. Phani Babu; Knutson, Daniel E; Sharmin, Dishary; Ahmed, Taukir; Rezvanian, Sepideh; Zahn, Nicolas M; Arnold, Leggy A.; Witkin, Jeffrey M.; Cook, James M.

doi:10.24820/ark.5550190.p011.398

Cited by 6 publications

(13 citation statements)

References 26 publications

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“…Given the pharmacological profile of KRM-II-81, chemistry in the imidazodiazepine structural series has continued (e.g., (Knutson et al, 2020;Pandey et al, 2020). In the present manuscript, the oral bioavailability, anticonvulsant activity, and sedative sideeffect profile of three structural analogs of KRM-II-81 (Fig.…”

Section: Introductionmentioning

confidence: 80%

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

Pandey

Divović

Rashid

et al. 2023

J Pharmacol Exp Ther

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Section: Introductionmentioning

confidence: 80%

“…FR-II-60 replaced the pyridine with a 2'-Cl phenyl group. Both KPP-III-34 and KPP-III-51 substituted the 1,3 oxazole with a 1,4 oxazole, known also to produce a non-sedating molecule like KRM-II-81 (compound 6 in Pandey et al, 2020). Ethyl substituents were added to the oxazoles as another structural change.…”

Section: Introductionmentioning

confidence: 99%

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

Pandey

Divović

Rashid

et al. 2023

J Pharmacol Exp Ther

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“…Halogen bonding with Phe100 located on α1 subunit is possible. Hydrogen bond interactions have been reported for other imidazodiazepines such as Hz166 with Ser205 . Amides PI310 and PI320 can additionally interact with Glu189 located on γ2 subunit.…”

Section: Results and Discussionmentioning

confidence: 91%

“…Hydrogen bond interactions have been reported for other imidazodiazepines such as Hz166 with Ser205. 30 Amides PI310 and PI320 can additionally interact with Glu189 located on γ2 subunit. The alkyl chain of both compounds is located on the periphery of the protein complex and is mostly exposed to water and hydrophilic amino acid residues.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Development of Inhaled GABA_A Receptor Modulators to Improve Airway Function in Bronchoconstrictive Disorders

Zahn

Roni

Yocum

et al. 2022

ACS Pharmacol. Transl. Sci.

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We report the modification of MIDD0301, an imidazodiazepine GABA A receptor (GABA A R) ligand, using two alkyl substituents. We developed PI310 with a 6-(4-phenylbutoxy)hexyl chain as used in the long-acting β2-agonist salmeterol and PI320 with a poly(ethylene glycol) chain as used to improve the brain:plasma ratio of naloxegol, a naloxone analogue. Both imidazodiazepines showed affinity toward the GABA A R binding site of clonazepam, with IC 50 values of 576 and 242 nM, respectively. Molecular docking analysis, using the available α 1 β 3 γ 2 GABA A R structural data, suggests binding of the diazepine core between the α1+/γ2− interface, whereas alkyl substituents are located outside the binding site and thus interact with the protein surface and solvent molecules. The physicochemical properties of these compounds are very different. The solubility of PI310 is low in water. PEGylation of PI320 significantly improves aqueous solubility and cell permeability. Neither compound is toxic in HEK293 cells following exposure at >300 μM for 18 h. Ex vivo studies using guinea pig tracheal rings showed that PI310 was unable to relax the constricted airway smooth muscle. In contrast, PI320 induced muscle relaxation at organ bath concentrations as low as 5 μM, with rapid onset (15 min) at 25 μM. PI320 also reduced airway hyper-responsiveness in vivo in a mouse model of steroid-resistant lung inflammation induced by intratracheal challenge with INFγ and lipopolysaccharide (LPS). At nebulized doses of 7.2 mg/kg, PI320 and albuterol were equally effective in reducing airway hyper-responsiveness. Ten minutes after nebulization, the lung concentration of PI320 was 50-fold that of PI310, indicating superior availability of PI320 when nebulized as an aqueous solution. Overall, PI320 is a promising inhaled drug candidate to quickly relax airway smooth muscle in bronchoconstrictive disorders, such as asthma. Future studies will evaluate the pharmacokinetic/ pharmacodynamic properties of PI320 when administered orally.

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“…Compounds, KRM-II-81 and its HCl salt, were synthesized by the Milwaukee group as previously described. ,, The other compounds were obtained from Sigma-Aldrich (St. Louis, Missouri).…”

Section: Methodsmentioning

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

Abstract: We dedicate this work to Professor Jan Bergman for his outstanding contributions to heterocyclic and organic chemistry as a whole

Cited by 6 publications

References 26 publications

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

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

Development of Inhaled GABA_A Receptor Modulators to Improve Airway Function in Bronchoconstrictive Disorders

Hydrochloride Salt of the GABAkine KRM-II-81

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

Abstract: We dedicate this work to Professor Jan Bergman for his outstanding contributions to heterocyclic and organic chemistry as a whole

Cited by 6 publications

References 26 publications

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

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

Development of Inhaled GABAA Receptor Modulators to Improve Airway Function in Bronchoconstrictive Disorders

Hydrochloride Salt of the GABAkine KRM-II-81

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Product

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Development of Inhaled GABA_A Receptor Modulators to Improve Airway Function in Bronchoconstrictive Disorders