Hydrochloride Salt of the GABAkine KRM-II-81
Authors
Mian, Md YeunusDivović, 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.
Article (Published version)
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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.
Source:
ACS Omega, 2022, 7, 31, 27550-27559Publisher:
- ACS Publications
Funding / projects:
- The authors thank the following granting agencies for support: DA011792, DA-043204, and NS-076517 and the National Science Foundation, Division of Chemistry [Grant CHE-1625735].
- Naval Research (Award No. N00014-15-WX-0-0149).
- Ministry of Education, Science and Technological Development, Republic of Serbia, Grant no. 200161 (University of Belgrade, Faculty of Pharmacy) (RS-200161)
DOI: 10.1021/acsomega.2c03029
ISSN: 2470-1343
WoS: 000886453700001
Scopus: 2-s2.0-85136154885
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PharmacyTY - 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 . .