Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3-selective GABAkine KRM-II-81
Samo za registrovane korisnike
2022
Autori
Golani, LalitDivović, 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
Članak u časopisu (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
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.
Ključne reči:
epilepsy / GABA / KRM-II-81 / metabolism / pharmacokineticsIzvor:
Biopharmaceutics and Drug Disposition, 2022, 43, 2, 66-75Izdavač:
- John Wiley and Sons Ltd
Finansiranje / projekti:
- DA‐ 043204 and NS‐076517 and the National Science Foundation, Divi- sion of Chemistry [Grant CHE‐1625735].
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200161 (Univerzitet u Beogradu, Farmaceutski fakultet) (RS-200161)
- Bihejvioralni efekti ponavljane primene novosintetisanih supstanci selektivnih za pojedine podtipove benzodiazepinskog mesta vezivanja GABA A receptora: poređenje sa standardnim psihofarmakološkim lekovima (RS-175076)
DOI: 10.1002/bdd.2313
ISSN: 0142-2782
WoS: 000766949300001
Scopus: 2-s2.0-85126005718
Institucija/grupa
PharmacyTY - 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 . .