TY  - JOUR
AU  - Mian, Md Yeunus
AU  - Divović, Branka
AU  - Sharmin, Dishary
AU  - Pandey, Kamal P.
AU  - Golani, Lalit K.
AU  - Tiruveedhula, V. V. N. Phani Babu
AU  - Cerne, Rok
AU  - Smith, Jodi L.
AU  - Ping, Xingjie
AU  - Jin, Xiaoming
AU  - Imler, Gregory H.
AU  - Deschamps, Jeffrey R.
AU  - Lippa, Arnold
AU  - Cook, James M.
AU  - Savić, Miroslav
AU  - Rowlett, James
AU  - Witkin, Jeffrey M.
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4363
AB  - 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 GABAA 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 1H NMR and 13C 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.
PB  - ACS Publications
T2  - ACS Omega
T1  - Hydrochloride Salt of the GABAkine KRM-II-81
VL  - 7
IS  - 31
SP  - 27550
EP  - 27559
DO  - 10.1021/acsomega.2c03029
ER  - 

@article{
author = "Mian, Md Yeunus and Divović, Branka and Sharmin, Dishary and Pandey, Kamal P. and Golani, Lalit K. and Tiruveedhula, V. V. N. Phani Babu and Cerne, Rok and Smith, Jodi L. and Ping, Xingjie and Jin, Xiaoming and Imler, Gregory H. and Deschamps, Jeffrey R. and Lippa, Arnold and Cook, James M. and Savić, Miroslav and Rowlett, James and Witkin, Jeffrey M.",
year = "2022",
abstract = "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 GABAA 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 1H NMR and 13C 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.",
publisher = "ACS Publications",
journal = "ACS Omega",
title = "Hydrochloride Salt of the GABAkine KRM-II-81",
volume = "7",
number = "31",
pages = "27550-27559",
doi = "10.1021/acsomega.2c03029"
}

Mian, M. Y., Divović, B., Sharmin, D., Pandey, K. P., Golani, L. K., Tiruveedhula, V. V. N. P. B., Cerne, R., Smith, J. L., Ping, X., Jin, X., Imler, G. H., Deschamps, J. R., Lippa, A., Cook, J. M., Savić, M., Rowlett, J.,& Witkin, J. M.. (2022). Hydrochloride Salt of the GABAkine KRM-II-81. in ACS Omega
ACS Publications., 7(31), 27550-27559.
https://doi.org/10.1021/acsomega.2c03029

Mian MY, Divović B, Sharmin D, Pandey KP, Golani LK, Tiruveedhula VVNPB, Cerne R, Smith JL, Ping X, Jin X, Imler GH, Deschamps JR, Lippa A, Cook JM, Savić M, Rowlett J, Witkin JM. Hydrochloride Salt of the GABAkine KRM-II-81. in ACS Omega. 2022;7(31):27550-27559.
doi:10.1021/acsomega.2c03029 .

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, Rowlett, James, Witkin, Jeffrey M., "Hydrochloride Salt of the GABAkine KRM-II-81" in ACS Omega, 7, no. 31 (2022):27550-27559,
https://doi.org/10.1021/acsomega.2c03029 . .