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 . .

TY  - JOUR
AU  - Clayton, Terry
AU  - Poe, Michael M.
AU  - Rallapalli, Sundari
AU  - Biawat, Poonam
AU  - Savić, Miroslav
AU  - Rowlett, James K.
AU  - Gallos, George
AU  - Emala, Charles
AU  - Kaczorowski, Catherine C.
AU  - Stafford, Douglas C.
AU  - Arnold, Leggy
AU  - Cook, James M.
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2317
AB  - An updated model of the GABA(A) benzodiazepine receptor pharmacophore of the alpha 5-BzR/GABA(A) subtype has been constructed prompted by the synthesis of subtype selective ligands in light of the recent developments in both ligand synthesis, behavioral studies, and molecular modeling studies of the binding site itself. A number of BzR/GABA(A) alpha 5 subtype selective compounds were synthesized, notably alpha 5-subtype selective inverse agonist PWZ-029 (1) which is active in enhancing cognition in both rodents and primates. In addition, a chiral positive allosteric modulator (PAM), SH-053-2'F-R-CH3 (2), has been shown to reverse the deleterious effects in the MAM-model of schizophrenia as well as alleviate constriction in airway smooth muscle. Presented here is an updated model of the pharmacophore for alpha 5 beta 2 gamma 2 Bz/GABA(A) receptors, including a rendering of PWZ-029 docked within the alpha 5-binding pocket showing specific interactions of the molecule with the receptor. Differences in the included volume as compared to alpha 1 beta 2 gamma 2, alpha 2 beta 2 gamma 2, and alpha 3 beta 2 gamma 2 will be illustrated for clarity. These new models enhance the ability to understand structural characteristics of ligands which act as agonists, antagonists, or inverse agonists at the Bz BS of GABA(A) receptors.
PB  - Hindawi Ltd, London
T2  - International Journal of Medicinal Chemistry
T1  - A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model
DO  - 10.1155/2015/430248
ER  - 

@article{
author = "Clayton, Terry and Poe, Michael M. and Rallapalli, Sundari and Biawat, Poonam and Savić, Miroslav and Rowlett, James K. and Gallos, George and Emala, Charles and Kaczorowski, Catherine C. and Stafford, Douglas C. and Arnold, Leggy and Cook, James M.",
year = "2015",
abstract = "An updated model of the GABA(A) benzodiazepine receptor pharmacophore of the alpha 5-BzR/GABA(A) subtype has been constructed prompted by the synthesis of subtype selective ligands in light of the recent developments in both ligand synthesis, behavioral studies, and molecular modeling studies of the binding site itself. A number of BzR/GABA(A) alpha 5 subtype selective compounds were synthesized, notably alpha 5-subtype selective inverse agonist PWZ-029 (1) which is active in enhancing cognition in both rodents and primates. In addition, a chiral positive allosteric modulator (PAM), SH-053-2'F-R-CH3 (2), has been shown to reverse the deleterious effects in the MAM-model of schizophrenia as well as alleviate constriction in airway smooth muscle. Presented here is an updated model of the pharmacophore for alpha 5 beta 2 gamma 2 Bz/GABA(A) receptors, including a rendering of PWZ-029 docked within the alpha 5-binding pocket showing specific interactions of the molecule with the receptor. Differences in the included volume as compared to alpha 1 beta 2 gamma 2, alpha 2 beta 2 gamma 2, and alpha 3 beta 2 gamma 2 will be illustrated for clarity. These new models enhance the ability to understand structural characteristics of ligands which act as agonists, antagonists, or inverse agonists at the Bz BS of GABA(A) receptors.",
publisher = "Hindawi Ltd, London",
journal = "International Journal of Medicinal Chemistry",
title = "A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model",
doi = "10.1155/2015/430248"
}

Clayton, T., Poe, M. M., Rallapalli, S., Biawat, P., Savić, M., Rowlett, J. K., Gallos, G., Emala, C., Kaczorowski, C. C., Stafford, D. C., Arnold, L.,& Cook, J. M.. (2015). A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model. in International Journal of Medicinal Chemistry
Hindawi Ltd, London..
https://doi.org/10.1155/2015/430248

Clayton T, Poe MM, Rallapalli S, Biawat P, Savić M, Rowlett JK, Gallos G, Emala C, Kaczorowski CC, Stafford DC, Arnold L, Cook JM. A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model. in International Journal of Medicinal Chemistry. 2015;.
doi:10.1155/2015/430248 .

Clayton, Terry, Poe, Michael M., Rallapalli, Sundari, Biawat, Poonam, Savić, Miroslav, Rowlett, James K., Gallos, George, Emala, Charles, Kaczorowski, Catherine C., Stafford, Douglas C., Arnold, Leggy, Cook, James M., "A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model" in International Journal of Medicinal Chemistry (2015),
https://doi.org/10.1155/2015/430248 . .

TY  - CONF
AU  - Huang, Shengming
AU  - Savić, Miroslav
AU  - Furtmueller, Roman
AU  - Duke, Angela
AU  - Clayton, Terry
AU  - Sieghart, Werner
AU  - Rowlett, James K.
AU  - Cook, James M.
PY  - 2007
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/940
PB  - Amer Chemical Soc, Washington
C3  - Abstracts of Papers of the American Chemical Society
T1  - Design and synthesis of stereoenantiomeric benzodiazepine receptor ligands
VL  - 233
SP  - 728
EP  - 728
UR  - https://hdl.handle.net/21.15107/rcub_farfar_940
ER  - 

@conference{
author = "Huang, Shengming and Savić, Miroslav and Furtmueller, Roman and Duke, Angela and Clayton, Terry and Sieghart, Werner and Rowlett, James K. and Cook, James M.",
year = "2007",
publisher = "Amer Chemical Soc, Washington",
journal = "Abstracts of Papers of the American Chemical Society",
title = "Design and synthesis of stereoenantiomeric benzodiazepine receptor ligands",
volume = "233",
pages = "728-728",
url = "https://hdl.handle.net/21.15107/rcub_farfar_940"
}

Huang, S., Savić, M., Furtmueller, R., Duke, A., Clayton, T., Sieghart, W., Rowlett, J. K.,& Cook, J. M.. (2007). Design and synthesis of stereoenantiomeric benzodiazepine receptor ligands. in Abstracts of Papers of the American Chemical Society
Amer Chemical Soc, Washington., 233, 728-728.
https://hdl.handle.net/21.15107/rcub_farfar_940

Huang S, Savić M, Furtmueller R, Duke A, Clayton T, Sieghart W, Rowlett JK, Cook JM. Design and synthesis of stereoenantiomeric benzodiazepine receptor ligands. in Abstracts of Papers of the American Chemical Society. 2007;233:728-728.
https://hdl.handle.net/21.15107/rcub_farfar_940 .

Huang, Shengming, Savić, Miroslav, Furtmueller, Roman, Duke, Angela, Clayton, Terry, Sieghart, Werner, Rowlett, James K., Cook, James M., "Design and synthesis of stereoenantiomeric benzodiazepine receptor ligands" in Abstracts of Papers of the American Chemical Society, 233 (2007):728-728,
https://hdl.handle.net/21.15107/rcub_farfar_940 .