New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy
Само за регистроване кориснике
2024
Аутори
Sharmin, DisharyDivović, Branka
Ping, Xingjie
Cerne, Rok
Smith, Jodi L.
Rezvanian, Sepideh
Mondal, Prithu
Michelle, Meyer Jean
Kiley, Molly E.
Arnold, Leggy A.
Mian, Md Yeunus
Pandey, Kamal P.
Jin, Xiaoming
Mitrović, Jelena
Đorović, Đorđe
Lippa, Arnold
Cook, James M.
Golani, Lalit K.
Scholze, Petra
Savić, Miroslav
Witkin, Jeffrey M.
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
KRM-II-81 (1) is an imidazodiazepine GABAA receptor (GABAAR) potentiator with broad antiseizure efficacy and a low sedative burden. A brominated analogue, DS-II-73 (5), was synthesized and pharmacologically characterized as a potential backup compound as KRM-II-81 moves forward into development. The synthesis from 2-amino-5-bromophenyl)(pyridin-2yl)methanone (6) was processed in five steps with an overall yield of 38% and without the need for a palladium catalyst. GABAAR binding occurred with a Ki of 150 nM, and only 3 of 41 screened binding sites produced inhibition ≥50% at 10 μM, and the potency to induce cytotoxicity was ≥240 mM. DS-II-73 was selective for α2/3/5- over that of α1-containing GABAARs. Oral exposure of plasma and brain of rats was more than sufficient to functionally impact GABAARs. Tonic convulsions in mice and lethality induced by pentylenetetrazol were suppressed by DS-II-73 after oral administration and latencies to clonic and tonic seizures were prolonged. Cortica...l slice preparations from a patient with pharmacoresistant epilepsy (mesial temporal lobe) showed decreases in the frequency of local field potentials by DS-II-73. As with KRM-II-81, the motor-impairing effects of DS-II-73 were low compared to diazepam. Molecular docking studies of DS-II-73 with the α1β3γ2L-configured GABAAR showed low interaction with α1His102 that is suggested as a potential molecular mechanism for its low sedative side effects. These findings support the viability of DS-II-73 as a backup molecule for its ethynyl analogue, KRM-II-81, with the human tissue data providing translational credibility.
Кључне речи:
pharmacokinetics / anticonvulsant / DS-II-73 / human epilepsy / imidazodiazepineИзвор:
ACS Chemical Neuroscience, 2024, 15, 3, 517-526Издавач:
- American Chemical Society
Финансирање / пројекти:
- Henry and Nelly Pence Foundation Trust AA029023, DA-043204, DA054177, NS-076517
- Milwaukee Institute of Drug Discovery
- UW-Milwaukee Shimadzu Laboratory for Advanced and Applied Analytical Chemistry
- University of Wisconsin-Milwaukee Research Foundation
DOI: 10.1021/acschemneuro.3c00555
ISSN: 1948-7193
PubMed: 38175916
WoS: 001158535100001
Scopus: 2-s2.0-85182005653
Институција/група
PharmacyTY - JOUR AU - Sharmin, Dishary AU - Divović, Branka AU - Ping, Xingjie AU - Cerne, Rok AU - Smith, Jodi L. AU - Rezvanian, Sepideh AU - Mondal, Prithu AU - Michelle, Meyer Jean AU - Kiley, Molly E. AU - Arnold, Leggy A. AU - Mian, Md Yeunus AU - Pandey, Kamal P. AU - Jin, Xiaoming AU - Mitrović, Jelena AU - Đorović, Đorđe AU - Lippa, Arnold AU - Cook, James M. AU - Golani, Lalit K. AU - Scholze, Petra AU - Savić, Miroslav AU - Witkin, Jeffrey M. PY - 2024 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5505 AB - KRM-II-81 (1) is an imidazodiazepine GABAA receptor (GABAAR) potentiator with broad antiseizure efficacy and a low sedative burden. A brominated analogue, DS-II-73 (5), was synthesized and pharmacologically characterized as a potential backup compound as KRM-II-81 moves forward into development. The synthesis from 2-amino-5-bromophenyl)(pyridin-2yl)methanone (6) was processed in five steps with an overall yield of 38% and without the need for a palladium catalyst. GABAAR binding occurred with a Ki of 150 nM, and only 3 of 41 screened binding sites produced inhibition ≥50% at 10 μM, and the potency to induce cytotoxicity was ≥240 mM. DS-II-73 was selective for α2/3/5- over that of α1-containing GABAARs. Oral exposure of plasma and brain of rats was more than sufficient to functionally impact GABAARs. Tonic convulsions in mice and lethality induced by pentylenetetrazol were suppressed by DS-II-73 after oral administration and latencies to clonic and tonic seizures were prolonged. Cortical slice preparations from a patient with pharmacoresistant epilepsy (mesial temporal lobe) showed decreases in the frequency of local field potentials by DS-II-73. As with KRM-II-81, the motor-impairing effects of DS-II-73 were low compared to diazepam. Molecular docking studies of DS-II-73 with the α1β3γ2L-configured GABAAR showed low interaction with α1His102 that is suggested as a potential molecular mechanism for its low sedative side effects. These findings support the viability of DS-II-73 as a backup molecule for its ethynyl analogue, KRM-II-81, with the human tissue data providing translational credibility. PB - American Chemical Society T2 - ACS Chemical Neuroscience T1 - New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy VL - 15 IS - 3 SP - 517 EP - 526 DO - 10.1021/acschemneuro.3c00555 ER -
@article{ author = "Sharmin, Dishary and Divović, Branka and Ping, Xingjie and Cerne, Rok and Smith, Jodi L. and Rezvanian, Sepideh and Mondal, Prithu and Michelle, Meyer Jean and Kiley, Molly E. and Arnold, Leggy A. and Mian, Md Yeunus and Pandey, Kamal P. and Jin, Xiaoming and Mitrović, Jelena and Đorović, Đorđe and Lippa, Arnold and Cook, James M. and Golani, Lalit K. and Scholze, Petra and Savić, Miroslav and Witkin, Jeffrey M.", year = "2024", abstract = "KRM-II-81 (1) is an imidazodiazepine GABAA receptor (GABAAR) potentiator with broad antiseizure efficacy and a low sedative burden. A brominated analogue, DS-II-73 (5), was synthesized and pharmacologically characterized as a potential backup compound as KRM-II-81 moves forward into development. The synthesis from 2-amino-5-bromophenyl)(pyridin-2yl)methanone (6) was processed in five steps with an overall yield of 38% and without the need for a palladium catalyst. GABAAR binding occurred with a Ki of 150 nM, and only 3 of 41 screened binding sites produced inhibition ≥50% at 10 μM, and the potency to induce cytotoxicity was ≥240 mM. DS-II-73 was selective for α2/3/5- over that of α1-containing GABAARs. Oral exposure of plasma and brain of rats was more than sufficient to functionally impact GABAARs. Tonic convulsions in mice and lethality induced by pentylenetetrazol were suppressed by DS-II-73 after oral administration and latencies to clonic and tonic seizures were prolonged. Cortical slice preparations from a patient with pharmacoresistant epilepsy (mesial temporal lobe) showed decreases in the frequency of local field potentials by DS-II-73. As with KRM-II-81, the motor-impairing effects of DS-II-73 were low compared to diazepam. Molecular docking studies of DS-II-73 with the α1β3γ2L-configured GABAAR showed low interaction with α1His102 that is suggested as a potential molecular mechanism for its low sedative side effects. These findings support the viability of DS-II-73 as a backup molecule for its ethynyl analogue, KRM-II-81, with the human tissue data providing translational credibility.", publisher = "American Chemical Society", journal = "ACS Chemical Neuroscience", title = "New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy", volume = "15", number = "3", pages = "517-526", doi = "10.1021/acschemneuro.3c00555" }
Sharmin, D., Divović, B., Ping, X., Cerne, R., Smith, J. L., Rezvanian, S., Mondal, P., Michelle, M. J., Kiley, M. E., Arnold, L. A., Mian, M. Y., Pandey, K. P., Jin, X., Mitrović, J., Đorović, Đ., Lippa, A., Cook, J. M., Golani, L. K., Scholze, P., Savić, M.,& Witkin, J. M.. (2024). New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy. in ACS Chemical Neuroscience American Chemical Society., 15(3), 517-526. https://doi.org/10.1021/acschemneuro.3c00555
Sharmin D, Divović B, Ping X, Cerne R, Smith JL, Rezvanian S, Mondal P, Michelle MJ, Kiley ME, Arnold LA, Mian MY, Pandey KP, Jin X, Mitrović J, Đorović Đ, Lippa A, Cook JM, Golani LK, Scholze P, Savić M, Witkin JM. New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy. in ACS Chemical Neuroscience. 2024;15(3):517-526. doi:10.1021/acschemneuro.3c00555 .
Sharmin, Dishary, Divović, Branka, Ping, Xingjie, Cerne, Rok, Smith, Jodi L., Rezvanian, Sepideh, Mondal, Prithu, Michelle, Meyer Jean, Kiley, Molly E., Arnold, Leggy A., Mian, Md Yeunus, Pandey, Kamal P., Jin, Xiaoming, Mitrović, Jelena, Đorović, Đorđe, Lippa, Arnold, Cook, James M., Golani, Lalit K., Scholze, Petra, Savić, Miroslav, Witkin, Jeffrey M., "New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy" in ACS Chemical Neuroscience, 15, no. 3 (2024):517-526, https://doi.org/10.1021/acschemneuro.3c00555 . .