TY  - JOUR
AU  - Golani, Lalit
AU  - Divović, Branka
AU  - Sharmin, Dishary
AU  - Pandey, Kamal
AU  - Mian, Md Yeunus
AU  - Cerne, Rok
AU  - Zahn, Nicolas
AU  - Meyer, Michelle
AU  - Tiruveedhula, Veera
AU  - Smith, Jodi
AU  - Ping, Xingjie
AU  - Jin, Xiaoming
AU  - Lippa, Arnold
AU  - Schkeryantz, Jeffrey
AU  - Arnold, Leggy
AU  - Cook, James
AU  - Savić, Miroslav
AU  - Witkin, Jeffrey
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4108
AB  - The 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 new α2/3‐selective GABAkine (gamma aminobutyric acid A receptor potentiator) with anticonvulsant, anxiolytic, and antinociceptive activity in preclinical models. Reducing metabolism was utilized as a means of potentially extending the half‐life of KRM‐II‐81. In vitro and in vivo studies were conducted to evaluate metabolic liabilities. Incubation of KRM‐II‐81 in hepatocytes revealed sites of potential metabolism on the oxazole and the diazepine rings. These sites were targeted in the design of a deuterated analog (D5‐KRM‐II‐ 81) that could be evaluated as a potentially longer‐acting analog. In contrast to computer predictions, peak plasma concentrations of D5‐KRM‐II‐81 in rats were not significantly greater than those produced by KRM‐II‐81 after oral administra- tion. Furthermore, brain disposition of KRM‐II‐81 was higher than that of D5‐KRM‐ II‐81. The half‐life of the two compounds in either plasma or brain did not statis- tically differ from one another but the tmax for D5‐KRM‐II‐81 occurred slightly earlier than for KRM‐II‐81. Non‐metabolic considerations might be relevant to the lack of increases in exposure by D5‐KRM‐II‐81. Alternative sites of metabolism on KRM‐II‐81, not targeted by the current deuteration process, are also possible. Despite its lack of augmented exposure, D5‐KRM‐II‐81, like KRM‐II‐81, significantly prevented seizures induced by pentylenetetrazol when given orally. The present findings introduce a new orally active anticonvulsant GABAkine, D5‐KRM‐II‐81.
PB  - John Wiley and Sons Ltd
T2  - Biopharmaceutics and Drug Disposition
T1  - Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3-selective GABAkine KRM-II-81
VL  - 43
IS  - 2
SP  - 66
EP  - 75
DO  - 10.1002/bdd.2313
ER  - 

@article{
author = "Golani, Lalit and Divović, Branka and Sharmin, Dishary and Pandey, Kamal and Mian, Md Yeunus and Cerne, Rok and Zahn, Nicolas and Meyer, Michelle and Tiruveedhula, Veera and Smith, Jodi and Ping, Xingjie and Jin, Xiaoming and Lippa, Arnold and Schkeryantz, Jeffrey and Arnold, Leggy and Cook, James and Savić, Miroslav and Witkin, Jeffrey",
year = "2022",
abstract = "The 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 new α2/3‐selective GABAkine (gamma aminobutyric acid A receptor potentiator) with anticonvulsant, anxiolytic, and antinociceptive activity in preclinical models. Reducing metabolism was utilized as a means of potentially extending the half‐life of KRM‐II‐81. In vitro and in vivo studies were conducted to evaluate metabolic liabilities. Incubation of KRM‐II‐81 in hepatocytes revealed sites of potential metabolism on the oxazole and the diazepine rings. These sites were targeted in the design of a deuterated analog (D5‐KRM‐II‐ 81) that could be evaluated as a potentially longer‐acting analog. In contrast to computer predictions, peak plasma concentrations of D5‐KRM‐II‐81 in rats were not significantly greater than those produced by KRM‐II‐81 after oral administra- tion. Furthermore, brain disposition of KRM‐II‐81 was higher than that of D5‐KRM‐ II‐81. The half‐life of the two compounds in either plasma or brain did not statis- tically differ from one another but the tmax for D5‐KRM‐II‐81 occurred slightly earlier than for KRM‐II‐81. Non‐metabolic considerations might be relevant to the lack of increases in exposure by D5‐KRM‐II‐81. Alternative sites of metabolism on KRM‐II‐81, not targeted by the current deuteration process, are also possible. Despite its lack of augmented exposure, D5‐KRM‐II‐81, like KRM‐II‐81, significantly prevented seizures induced by pentylenetetrazol when given orally. The present findings introduce a new orally active anticonvulsant GABAkine, D5‐KRM‐II‐81.",
publisher = "John Wiley and Sons Ltd",
journal = "Biopharmaceutics and Drug Disposition",
title = "Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3-selective GABAkine KRM-II-81",
volume = "43",
number = "2",
pages = "66-75",
doi = "10.1002/bdd.2313"
}

Golani, L., Divović, B., Sharmin, D., Pandey, K., Mian, M. Y., Cerne, R., Zahn, N., Meyer, M., Tiruveedhula, V., Smith, J., Ping, X., Jin, X., Lippa, A., Schkeryantz, J., Arnold, L., Cook, J., Savić, M.,& Witkin, J.. (2022). Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3-selective GABAkine KRM-II-81. in Biopharmaceutics and Drug Disposition
John Wiley and Sons Ltd., 43(2), 66-75.
https://doi.org/10.1002/bdd.2313

Golani L, Divović B, Sharmin D, Pandey K, Mian MY, Cerne R, Zahn N, Meyer M, Tiruveedhula V, Smith J, Ping X, Jin X, Lippa A, Schkeryantz J, Arnold L, Cook J, Savić M, Witkin J. Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3-selective GABAkine KRM-II-81. in Biopharmaceutics and Drug Disposition. 2022;43(2):66-75.
doi:10.1002/bdd.2313 .

Golani, Lalit, Divović, Branka, Sharmin, Dishary, Pandey, Kamal, Mian, Md Yeunus, Cerne, Rok, Zahn, Nicolas, Meyer, Michelle, Tiruveedhula, Veera, Smith, Jodi, Ping, Xingjie, Jin, Xiaoming, Lippa, Arnold, Schkeryantz, Jeffrey, Arnold, Leggy, Cook, James, Savić, Miroslav, Witkin, Jeffrey, "Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3-selective GABAkine KRM-II-81" in Biopharmaceutics and Drug Disposition, 43, no. 2 (2022):66-75,
https://doi.org/10.1002/bdd.2313 . .

TY  - CONF
AU  - Knutson, Daniel
AU  - Kodali, Revathi
AU  - Stephen, Michael
AU  - Verma, Ranjit
AU  - Witzigmann, Christopher
AU  - Meirelles, Matheus
AU  - Zahn, Nicolas
AU  - Huber, Alec
AU  - Arnold, Leggy
AU  - Savić, Miroslav
AU  - Ernst, Margot
AU  - Sieghart, Werner
AU  - Cook, James M.
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3234
PB  - Amer Chemical Soc, Washington
C3  - Abstracts of Papers of the American Chemical Society
T1  - Design and synthesis of novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability
VL  - 255
UR  - https://hdl.handle.net/21.15107/rcub_farfar_3234
ER  - 

@conference{
author = "Knutson, Daniel and Kodali, Revathi and Stephen, Michael and Verma, Ranjit and Witzigmann, Christopher and Meirelles, Matheus and Zahn, Nicolas and Huber, Alec and Arnold, Leggy and Savić, Miroslav and Ernst, Margot and Sieghart, Werner and Cook, James M.",
year = "2018",
publisher = "Amer Chemical Soc, Washington",
journal = "Abstracts of Papers of the American Chemical Society",
title = "Design and synthesis of novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability",
volume = "255",
url = "https://hdl.handle.net/21.15107/rcub_farfar_3234"
}

Knutson, D., Kodali, R., Stephen, M., Verma, R., Witzigmann, C., Meirelles, M., Zahn, N., Huber, A., Arnold, L., Savić, M., Ernst, M., Sieghart, W.,& Cook, J. M.. (2018). Design and synthesis of novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability. in Abstracts of Papers of the American Chemical Society
Amer Chemical Soc, Washington., 255.
https://hdl.handle.net/21.15107/rcub_farfar_3234

Knutson D, Kodali R, Stephen M, Verma R, Witzigmann C, Meirelles M, Zahn N, Huber A, Arnold L, Savić M, Ernst M, Sieghart W, Cook JM. Design and synthesis of novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability. in Abstracts of Papers of the American Chemical Society. 2018;255.
https://hdl.handle.net/21.15107/rcub_farfar_3234 .

Knutson, Daniel, Kodali, Revathi, Stephen, Michael, Verma, Ranjit, Witzigmann, Christopher, Meirelles, Matheus, Zahn, Nicolas, Huber, Alec, Arnold, Leggy, Savić, Miroslav, Ernst, Margot, Sieghart, Werner, Cook, James M., "Design and synthesis of novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability" in Abstracts of Papers of the American Chemical Society, 255 (2018),
https://hdl.handle.net/21.15107/rcub_farfar_3234 .

TY  - JOUR
AU  - Knutson, Daniel
AU  - Kodali, Revathi
AU  - Divović, Branka
AU  - Treven, Marco
AU  - Stephen, Michael
AU  - Zahn, Nicolas
AU  - Dobričić, Vladimir
AU  - Huber, Alec
AU  - Meirelles, Matheus
AU  - Verma, Ranjit
AU  - Wimmer, Laurin
AU  - Witzigmann, Christopher
AU  - Arnold, Leggy
AU  - Chiou, Lih-Chu
AU  - Ernst, Margot
AU  - Mihovilović, Marko D.
AU  - Savić, Miroslav
AU  - Sieghart, Werner
AU  - Cook, James M.
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3147
AB  - Recent reports indicate that alpha 6/beta 2/3 gamma 2 GABA(A)R selective ligands may be important for the treatment of trigeminal activation-related pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally alpha 6/beta 2/3 gamma 2 GABA(A)R selective pyrazoloquinolinones, 42 novel analogs were synthesized, and their in vitro metabolic stability and cytotoxicity as well as their in vivo pharmacokinetics, basic behavioral pharmacology, and effects on locomotion were investigated. Incorporation of deuterium into the methoxy substituents of the ligands increased their duration of action via improved metabolic stability and bioavailability, while their selectivity for the GABA(A)R a alpha 6 subtype was retained. 8b was identified as the lead compound with a substantially improved pharmacokinetic profile. The ligands allosterically modulated diazepam insensitive alpha 6/beta 2/3 gamma 2 GABA(A)Rs and were functionally silent at diazepam sensitive alpha 6/beta 2/3 gamma 2 GABA(A)Rs, thus no sedation was detected. In addition, these analogs were not cytotoxic, which render them interesting candidates for treatment of CNS disorders mediated by GABA(A)R alpha 6/beta 2/3 gamma 2 subtypes.
PB  - Amer Chemical Soc, Washington
T2  - Journal of Medicinal Chemistry
T1  - Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABA(A)R) alpha 6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability
VL  - 61
IS  - 6
SP  - 2422
EP  - 2446
DO  - 10.1021/acs.jmedchem.7b01664
ER  - 

@article{
author = "Knutson, Daniel and Kodali, Revathi and Divović, Branka and Treven, Marco and Stephen, Michael and Zahn, Nicolas and Dobričić, Vladimir and Huber, Alec and Meirelles, Matheus and Verma, Ranjit and Wimmer, Laurin and Witzigmann, Christopher and Arnold, Leggy and Chiou, Lih-Chu and Ernst, Margot and Mihovilović, Marko D. and Savić, Miroslav and Sieghart, Werner and Cook, James M.",
year = "2018",
abstract = "Recent reports indicate that alpha 6/beta 2/3 gamma 2 GABA(A)R selective ligands may be important for the treatment of trigeminal activation-related pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally alpha 6/beta 2/3 gamma 2 GABA(A)R selective pyrazoloquinolinones, 42 novel analogs were synthesized, and their in vitro metabolic stability and cytotoxicity as well as their in vivo pharmacokinetics, basic behavioral pharmacology, and effects on locomotion were investigated. Incorporation of deuterium into the methoxy substituents of the ligands increased their duration of action via improved metabolic stability and bioavailability, while their selectivity for the GABA(A)R a alpha 6 subtype was retained. 8b was identified as the lead compound with a substantially improved pharmacokinetic profile. The ligands allosterically modulated diazepam insensitive alpha 6/beta 2/3 gamma 2 GABA(A)Rs and were functionally silent at diazepam sensitive alpha 6/beta 2/3 gamma 2 GABA(A)Rs, thus no sedation was detected. In addition, these analogs were not cytotoxic, which render them interesting candidates for treatment of CNS disorders mediated by GABA(A)R alpha 6/beta 2/3 gamma 2 subtypes.",
publisher = "Amer Chemical Soc, Washington",
journal = "Journal of Medicinal Chemistry",
title = "Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABA(A)R) alpha 6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability",
volume = "61",
number = "6",
pages = "2422-2446",
doi = "10.1021/acs.jmedchem.7b01664"
}

Knutson, D., Kodali, R., Divović, B., Treven, M., Stephen, M., Zahn, N., Dobričić, V., Huber, A., Meirelles, M., Verma, R., Wimmer, L., Witzigmann, C., Arnold, L., Chiou, L., Ernst, M., Mihovilović, M. D., Savić, M., Sieghart, W.,& Cook, J. M.. (2018). Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABA(A)R) alpha 6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability. in Journal of Medicinal Chemistry
Amer Chemical Soc, Washington., 61(6), 2422-2446.
https://doi.org/10.1021/acs.jmedchem.7b01664

Knutson D, Kodali R, Divović B, Treven M, Stephen M, Zahn N, Dobričić V, Huber A, Meirelles M, Verma R, Wimmer L, Witzigmann C, Arnold L, Chiou L, Ernst M, Mihovilović MD, Savić M, Sieghart W, Cook JM. Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABA(A)R) alpha 6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability. in Journal of Medicinal Chemistry. 2018;61(6):2422-2446.
doi:10.1021/acs.jmedchem.7b01664 .

Knutson, Daniel, Kodali, Revathi, Divović, Branka, Treven, Marco, Stephen, Michael, Zahn, Nicolas, Dobričić, Vladimir, Huber, Alec, Meirelles, Matheus, Verma, Ranjit, Wimmer, Laurin, Witzigmann, Christopher, Arnold, Leggy, Chiou, Lih-Chu, Ernst, Margot, Mihovilović, Marko D., Savić, Miroslav, Sieghart, Werner, Cook, James M., "Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABA(A)R) alpha 6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability" in Journal of Medicinal Chemistry, 61, no. 6 (2018):2422-2446,
https://doi.org/10.1021/acs.jmedchem.7b01664 . .