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Hydrochloride Salt of the GABAkine KRM-II-81
[Image: see text] 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 potentiator of GABA(A) receptors (a GABAkine) undergoing preparation for clinical development. KRM-II-81 is active against many seizure and pain models in roden...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9366947/ https://www.ncbi.nlm.nih.gov/pubmed/35967038 http://dx.doi.org/10.1021/acsomega.2c03029 |
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author | Mian, Md Yeunus Divović, Branka Sharmin, Dishary Pandey, Kamal P. Golani, Lalit K. Tiruveedhula, V. V. N. Phani Babu Cerne, Rok Smith, Jodi L. Ping, Xingjie Jin, Xiaoming Imler, Gregory H. Deschamps, Jeffrey R. Lippa, Arnold Cook, James M. Savić, Miroslav M. Rowlett, James Witkin, Jeffrey M. |
author_facet | Mian, Md Yeunus Divović, Branka Sharmin, Dishary Pandey, Kamal P. Golani, Lalit K. Tiruveedhula, V. V. N. Phani Babu Cerne, Rok Smith, Jodi L. Ping, Xingjie Jin, Xiaoming Imler, Gregory H. Deschamps, Jeffrey R. Lippa, Arnold Cook, James M. Savić, Miroslav M. Rowlett, James Witkin, Jeffrey M. |
author_sort | Mian, Md Yeunus |
collection | PubMed |
description | [Image: see text] 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 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. |
format | Online Article Text |
id | pubmed-9366947 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-93669472022-08-12 Hydrochloride Salt of the GABAkine KRM-II-81 Mian, Md Yeunus Divović, Branka Sharmin, Dishary Pandey, Kamal P. Golani, Lalit K. Tiruveedhula, V. V. N. Phani Babu Cerne, Rok Smith, Jodi L. Ping, Xingjie Jin, Xiaoming Imler, Gregory H. Deschamps, Jeffrey R. Lippa, Arnold Cook, James M. Savić, Miroslav M. Rowlett, James Witkin, Jeffrey M. ACS Omega [Image: see text] 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 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. American Chemical Society 2022-07-27 /pmc/articles/PMC9366947/ /pubmed/35967038 http://dx.doi.org/10.1021/acsomega.2c03029 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Mian, Md Yeunus Divović, Branka Sharmin, Dishary Pandey, Kamal P. Golani, Lalit K. Tiruveedhula, V. V. N. Phani Babu Cerne, Rok Smith, Jodi L. Ping, Xingjie Jin, Xiaoming Imler, Gregory H. Deschamps, Jeffrey R. Lippa, Arnold Cook, James M. Savić, Miroslav M. Rowlett, James Witkin, Jeffrey M. Hydrochloride Salt of the GABAkine KRM-II-81 |
title | Hydrochloride Salt
of the GABAkine KRM-II-81 |
title_full | Hydrochloride Salt
of the GABAkine KRM-II-81 |
title_fullStr | Hydrochloride Salt
of the GABAkine KRM-II-81 |
title_full_unstemmed | Hydrochloride Salt
of the GABAkine KRM-II-81 |
title_short | Hydrochloride Salt
of the GABAkine KRM-II-81 |
title_sort | hydrochloride salt
of the gabakine krm-ii-81 |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9366947/ https://www.ncbi.nlm.nih.gov/pubmed/35967038 http://dx.doi.org/10.1021/acsomega.2c03029 |
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