The Experts below are selected from a list of 246 Experts worldwide ranked by ideXlab platform
Pankaja K. Kadaba - One of the best experts on this subject based on the ideXlab platform.
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Aminoalkylpyridines (AAPs), triazoline metabolite analogues, as anticonvulsants highly effective in the MES test.
Current medicinal chemistry, 2003Co-Authors: Pankaja K. Kadaba, Trupti DixitAbstract:Elucidation of the metabolism and pharmacology of 1,2,3-Triazolines (TRs) led to the identification of the triazoline pharmacophore and the evolution of the aminoalkylpyridines (AAPs). The AAPs have no activity in the scMet test but are highly effective in the MES seizure test by the oral route. The AAPs bind to the sigma(1) receptor with low affinity, but high selectivity. They impair Glu release to the same extent as the Triazolines and afforded a high degree of protection in the kindled rat. They show no affinity for the NMDA/PCP receptor sites; thus the toxic side effects of NMDA antagonists are absent in the sigma selective AAPs. Variations of the heterocyclic unit, the alkyl chain and the amino group in the AAP leads, indicated that the 4-pyridyl substituent along with a methyl (alkyl) group, and a 4-C1, 3-C1 or 3,4-C1(2) substitution on the N-phenyl group, afforded the most active compounds. Amino group modification by acylation did not improve activity. The hydrazone compounds were the most active. Although the AAPs are very effective in the MES and the kindling models of epilepsy, they showed only low to moderate activity in protecting neuronal cells in stroke-induced cerebral ischemia. In the case of the TR compounds, even the least effective TR afforded 47% protection from neuronal injury. It is not known at this point, whether activity in both the MES and scMet tests, which would imply a role for both Glu and GABA, is a prerequisite for antiischemic activity.
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Rational Drug Design and the Discovery of the Δ2-1,2,3-Triazolines, A Unique Class of Anticonvulsant and Antiischemic Agents
Current medicinal chemistry, 2003Co-Authors: Pankaja K. KadabaAbstract:The delta(2)- 1,2,3- triazoline anticonvulsants (TRs) may be considered as representing a unique class of "built-in" heterocyclic prodrugs where the active "structure element" is an integral part of the ring system and can be identified only by a knowledge of their chemical reactivity and metabolism. Investigations on the metabolism and pharmacology of a lead triazoline, ADD17014 suggest that the Triazolines function as "prodrugs" and exert their anticonvulsant activity by impairing excitatory amino acid (EAA) L-Glutamate (L-Glu) neurotransmission via a unique "dual-action" mechanism. While an active primary beta-amino alcohol metabolite from the parent prodrug acts as an N-methyl-D-aspartate (NMDA)/MK -801 receptor antagonist, the parent triazoline impairs the presynaptic release of L-Glu. Various pieces of theoretical reasoning and experimental evidence have led to the clucidation of the dual-action mechanism. Based on the unique chemistry of the Triazolines, and their metabolic pathways, biotransformation products of TRs were predicted to be the beta-amino alcohols V and VA, the alpha-amino acid VI, the triazole VII, the aziridine VIII and the ketimine IX. In vivo and in vitro pharmacological studies of the TR and potential metabolites, along with a full quantitative urinary metabolic profiling of TR indicated the primary beta-amino alcohol V as the active species. It was the only compound that inhibited the specific binding of [3H]MK-801 to the MK-801 site, 56% at 10 micro M drug concentration, but itself had no anticonvulsant activity, suggesting TR acted as a prodrug. Three metabolites were identified; V was the most predominant (45.7 +/- 7.6) % of administered drug, with lesser amounts of VA, (17.3 +/- 5.1) % and very minor amounts of aziridine VIII (4.0 +/- 0.02)%. Since only VIII can yield VA, its formation indicated that the biotransformation of TR occurred, at least in part, through aziridine. No amino acid metabolite was detected, which implied that no in vivo oxidation of V or oxidative biotransformation of TR or aziridine by hydroxylation at the methylene group occurred. While triazoline significantly decreased Ca(2+) -dependent, k(+)-evoked L-Glu release (83% at 100 micro M drug concentration ), some Triazolines showed an augmentation of 50-63%, in the Cl(-) channel activity, a useful membrane action that reduces the excessive L-Glu release that occurs during epileptic seizures. The high anticonvulsant activity of TRs in a variety of seizure models including their effectiveness in the kindling model of complex partial seizures may be due to their unique dual-action mechanism whereby the TR and V together effectively impair both pre- and postsynaptic aspects of EAA neurotransmission; thus the TRs have clinical potential in the treatment of complex partial epilepsy which is refractory to currently available drugs. Since there is strong evidence that L-Glu plays an important role in human epilepsy as well as in brain ischemia/stroke, and since the TRs act by inhibiting EAA neurotransmission, it was logical to expect that the anticonvulsant TRs may evince beneficial therapeutic potential in cerebral ischemia resulting from stroke as well. And indeed, several TRs, when tested in the standard gerbil model of global ischemia did evince remarkable ability to prevent neuronal death.
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Triazolines xxxiii nonregiospecific 1 3 cycloaddition of aryl azides to vinylpyridines a unique route to the synthesis of 2 pyridyl substituted aziridines via unstable 4 pyridyltriazoline intermediates
Journal of Heterocyclic Chemistry, 1997Co-Authors: Zhaiwei Lin, Pankaja K. KadabaAbstract:The 1,3-cycloaddition of aryl azides to the olefinic bonds of 4- and 2-vinylpyridines has been found to yield pyridyl substituted aziridines as the main reaction products with only smaller amounts of the normally expected l-aryl-5-pyridyl-1,2,3-triazolincs. Theoretical and experimental evidence are provided to explain the results: based on the fact that the olefinic bonds in 4- and 2-vinylpyridines are electron-deficient, azide addition can be expected to be not regiospecific. In the bidirectional addition reaction, the HOMOazide- LUMOolefin interaction predominates leading to unstable l-aryl-4-pyridyl-1,2,3-Triazolines, which, unlike the more stable 5-pyridyl compounds, lose nitrogen under thermal conditions to yield the aziridines. At room temperature, the reactions yield the aziridine along with the l-aryl-4-pyridyltriazole, providing evidence for the formation of the 4-pyridyltriazoline intermediate. Reaction of the vinylpyridines with variously substituted phenyl azides, clearly indicates that the electron donating methyl and methoxy groups on the phenyl azide facilitate reaction, while the electron withdrawing nitro group has a retarding effect. This is consistent with an increase in the HOMOazide energy and hence in azide reactivity. According to the FMO model, the 1,3-cycloaddition of aryl azides to vinylpyridines appears to be predominantly, but not exclusively, a HOMOazide-LUMOolefin interaction and provides a unique route to the synthesis of 2-pyridyl substituted aziridines.
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Triazolines xxvii δ2 1 2 3 triazoline anticonvulsants novel built in heterocyclic prodrugs with a unique dual action mechanism for impairing excitatory amino acid l glutamate neurotransmission
Bioorganic & Medicinal Chemistry, 1996Co-Authors: Pankaja K. Kadaba, Paul J. Stevenson, Ivo Pnnane, L.a. DamaniAbstract:The delta2-1,2,3-triazoline anticonvulsants (1) may be considered as representing a unique class of 'built-in' heterocyclic prodrugs where the active 'structure element' is an integral part of the ring system and can be identified only by a knowledge of their chemical reactivity and metabolism. Investigations on the metabolism and pharmacology of a lead triazoline, ADD17014 (1a), suggest that the Triazolines function as 'prodrugs' and exert their anticonvulsant activity by impairing excitatory amino acid (EAA) L-glutamate (L-Glu) neurotransmission via a unique 'dual-action' mechanism. While an active beta-amino alcohol metabolite, 2a, from the parent prodrug acts as an N-methyl-D-aspartate (NMDA)/MK-801 receptor antagonist, the parent triazoline impairs the presynaptic release of L-Glu. Various pieces of theoretical reasoning and experimental evidence led to the elucidation of the dual-action mechanism. Based on the unique chemistry of the Triazolines, the potential metabolic pathways and biotransformation products of 1a were predicted to be the beta-amino alcohols 2a and 2a', the alpha-amino acid 3a, the triazole 4a, the aziridine 5a, and the ketimine 6a. In vivo and in vitro pharmacological studies of 1a and potential metabolities, along with a full quantitative urinary metabolic profiling of 1a, indicated the beta-amino alcohol 2a as the active species. It was the only compound that inhibited the specific binding of [3H]MK-801 to the MK-801 site, 56% at 10 microM drug concentration, but itself had no anticonvulsant activity, suggesting 1a acted as a prodrug. Three metabolites were identified; 2a was the most predominant, with lesser amounts of 2a', and very minor amounts of aziridine 5a. Since only 5a can yield 2a', its formation indicated that the biotransformation of 1a occurred, at least in part, through 5a. No amino acid metabolite 3a was detected, which implied that no in vivo oxidation of 2a or oxidative biotransformation of 1a or 5a by hydroxylation at the methylene group occurred. While triazoline 1a significantly decreased Ca2(+)-dependent, K(+)-evoked L-Glu release (83% at 100 microM drug concentration), Triazolines 1a-1c showed an augmentation of 50-63%, in the Cl- channel activity, a useful membrane action that reduces the excessive L-Glu release that occurs during epileptic seizures. The high anticonvulsant activity of 1a may be due to its unique dual-action mechanism whereby 1a and 2a together effectively impair both pre- and postsynaptic aspects of EAA neurotransmission, and has clinical potential in complex partial epilepsy which is refractory to currently available drugs.
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Triazolines—XXVII. Δ2-1,2,3-triazoline anticonvulsants: Novel ‘built-in’ heterocyclic prodrugs with a unique ‘dual-action’ mechanism for impairing excitatory amino acid l-glutamate neurotransmission
Bioorganic & medicinal chemistry, 1996Co-Authors: Pankaja K. Kadaba, Paul J. Stevenson, Ivo P-nnane, L.a. DamaniAbstract:The delta2-1,2,3-triazoline anticonvulsants (1) may be considered as representing a unique class of 'built-in' heterocyclic prodrugs where the active 'structure element' is an integral part of the ring system and can be identified only by a knowledge of their chemical reactivity and metabolism. Investigations on the metabolism and pharmacology of a lead triazoline, ADD17014 (1a), suggest that the Triazolines function as 'prodrugs' and exert their anticonvulsant activity by impairing excitatory amino acid (EAA) L-glutamate (L-Glu) neurotransmission via a unique 'dual-action' mechanism. While an active beta-amino alcohol metabolite, 2a, from the parent prodrug acts as an N-methyl-D-aspartate (NMDA)/MK-801 receptor antagonist, the parent triazoline impairs the presynaptic release of L-Glu. Various pieces of theoretical reasoning and experimental evidence led to the elucidation of the dual-action mechanism. Based on the unique chemistry of the Triazolines, the potential metabolic pathways and biotransformation products of 1a were predicted to be the beta-amino alcohols 2a and 2a', the alpha-amino acid 3a, the triazole 4a, the aziridine 5a, and the ketimine 6a. In vivo and in vitro pharmacological studies of 1a and potential metabolities, along with a full quantitative urinary metabolic profiling of 1a, indicated the beta-amino alcohol 2a as the active species. It was the only compound that inhibited the specific binding of [3H]MK-801 to the MK-801 site, 56% at 10 microM drug concentration, but itself had no anticonvulsant activity, suggesting 1a acted as a prodrug. Three metabolites were identified; 2a was the most predominant, with lesser amounts of 2a', and very minor amounts of aziridine 5a. Since only 5a can yield 2a', its formation indicated that the biotransformation of 1a occurred, at least in part, through 5a. No amino acid metabolite 3a was detected, which implied that no in vivo oxidation of 2a or oxidative biotransformation of 1a or 5a by hydroxylation at the methylene group occurred. While triazoline 1a significantly decreased Ca2(+)-dependent, K(+)-evoked L-Glu release (83% at 100 microM drug concentration), Triazolines 1a-1c showed an augmentation of 50-63%, in the Cl- channel activity, a useful membrane action that reduces the excessive L-Glu release that occurs during epileptic seizures. The high anticonvulsant activity of 1a may be due to its unique dual-action mechanism whereby 1a and 2a together effectively impair both pre- and postsynaptic aspects of EAA neurotransmission, and has clinical potential in complex partial epilepsy which is refractory to currently available drugs.
L.a. Damani - One of the best experts on this subject based on the ideXlab platform.
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Triazolines xxvii δ2 1 2 3 triazoline anticonvulsants novel built in heterocyclic prodrugs with a unique dual action mechanism for impairing excitatory amino acid l glutamate neurotransmission
Bioorganic & Medicinal Chemistry, 1996Co-Authors: Pankaja K. Kadaba, Paul J. Stevenson, Ivo Pnnane, L.a. DamaniAbstract:The delta2-1,2,3-triazoline anticonvulsants (1) may be considered as representing a unique class of 'built-in' heterocyclic prodrugs where the active 'structure element' is an integral part of the ring system and can be identified only by a knowledge of their chemical reactivity and metabolism. Investigations on the metabolism and pharmacology of a lead triazoline, ADD17014 (1a), suggest that the Triazolines function as 'prodrugs' and exert their anticonvulsant activity by impairing excitatory amino acid (EAA) L-glutamate (L-Glu) neurotransmission via a unique 'dual-action' mechanism. While an active beta-amino alcohol metabolite, 2a, from the parent prodrug acts as an N-methyl-D-aspartate (NMDA)/MK-801 receptor antagonist, the parent triazoline impairs the presynaptic release of L-Glu. Various pieces of theoretical reasoning and experimental evidence led to the elucidation of the dual-action mechanism. Based on the unique chemistry of the Triazolines, the potential metabolic pathways and biotransformation products of 1a were predicted to be the beta-amino alcohols 2a and 2a', the alpha-amino acid 3a, the triazole 4a, the aziridine 5a, and the ketimine 6a. In vivo and in vitro pharmacological studies of 1a and potential metabolities, along with a full quantitative urinary metabolic profiling of 1a, indicated the beta-amino alcohol 2a as the active species. It was the only compound that inhibited the specific binding of [3H]MK-801 to the MK-801 site, 56% at 10 microM drug concentration, but itself had no anticonvulsant activity, suggesting 1a acted as a prodrug. Three metabolites were identified; 2a was the most predominant, with lesser amounts of 2a', and very minor amounts of aziridine 5a. Since only 5a can yield 2a', its formation indicated that the biotransformation of 1a occurred, at least in part, through 5a. No amino acid metabolite 3a was detected, which implied that no in vivo oxidation of 2a or oxidative biotransformation of 1a or 5a by hydroxylation at the methylene group occurred. While triazoline 1a significantly decreased Ca2(+)-dependent, K(+)-evoked L-Glu release (83% at 100 microM drug concentration), Triazolines 1a-1c showed an augmentation of 50-63%, in the Cl- channel activity, a useful membrane action that reduces the excessive L-Glu release that occurs during epileptic seizures. The high anticonvulsant activity of 1a may be due to its unique dual-action mechanism whereby 1a and 2a together effectively impair both pre- and postsynaptic aspects of EAA neurotransmission, and has clinical potential in complex partial epilepsy which is refractory to currently available drugs.
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Triazolines—XXVII. Δ2-1,2,3-triazoline anticonvulsants: Novel ‘built-in’ heterocyclic prodrugs with a unique ‘dual-action’ mechanism for impairing excitatory amino acid l-glutamate neurotransmission
Bioorganic & medicinal chemistry, 1996Co-Authors: Pankaja K. Kadaba, Paul J. Stevenson, Ivo P-nnane, L.a. DamaniAbstract:The delta2-1,2,3-triazoline anticonvulsants (1) may be considered as representing a unique class of 'built-in' heterocyclic prodrugs where the active 'structure element' is an integral part of the ring system and can be identified only by a knowledge of their chemical reactivity and metabolism. Investigations on the metabolism and pharmacology of a lead triazoline, ADD17014 (1a), suggest that the Triazolines function as 'prodrugs' and exert their anticonvulsant activity by impairing excitatory amino acid (EAA) L-glutamate (L-Glu) neurotransmission via a unique 'dual-action' mechanism. While an active beta-amino alcohol metabolite, 2a, from the parent prodrug acts as an N-methyl-D-aspartate (NMDA)/MK-801 receptor antagonist, the parent triazoline impairs the presynaptic release of L-Glu. Various pieces of theoretical reasoning and experimental evidence led to the elucidation of the dual-action mechanism. Based on the unique chemistry of the Triazolines, the potential metabolic pathways and biotransformation products of 1a were predicted to be the beta-amino alcohols 2a and 2a', the alpha-amino acid 3a, the triazole 4a, the aziridine 5a, and the ketimine 6a. In vivo and in vitro pharmacological studies of 1a and potential metabolities, along with a full quantitative urinary metabolic profiling of 1a, indicated the beta-amino alcohol 2a as the active species. It was the only compound that inhibited the specific binding of [3H]MK-801 to the MK-801 site, 56% at 10 microM drug concentration, but itself had no anticonvulsant activity, suggesting 1a acted as a prodrug. Three metabolites were identified; 2a was the most predominant, with lesser amounts of 2a', and very minor amounts of aziridine 5a. Since only 5a can yield 2a', its formation indicated that the biotransformation of 1a occurred, at least in part, through 5a. No amino acid metabolite 3a was detected, which implied that no in vivo oxidation of 2a or oxidative biotransformation of 1a or 5a by hydroxylation at the methylene group occurred. While triazoline 1a significantly decreased Ca2(+)-dependent, K(+)-evoked L-Glu release (83% at 100 microM drug concentration), Triazolines 1a-1c showed an augmentation of 50-63%, in the Cl- channel activity, a useful membrane action that reduces the excessive L-Glu release that occurs during epileptic seizures. The high anticonvulsant activity of 1a may be due to its unique dual-action mechanism whereby 1a and 2a together effectively impair both pre- and postsynaptic aspects of EAA neurotransmission, and has clinical potential in complex partial epilepsy which is refractory to currently available drugs.
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Triazolines. XXI: Preformulation Degradation Kinetics and Chemical Stability of a Novel Triazoline Anticonvulsant
Journal of Pharmaceutical Sciences, 1992Co-Authors: M.a. Freeke Hamelijnck, Paul J. Stevenson, Pankaja K. Kadaba, L.a. DamaniAbstract:Abstract The effect of pH, temperature, and two buffer species (citric acid‐phosphate and bicarbonate‐carbonate) on the stability of 1‐(4‐chlorophenyl)‐5‐(4‐pyridyl)‐Δ 2 ‐1,2,3‐triazoline (ADD17014; 1), a novel triazoline anticonvulsant, was determined by HPLC. One of the main degradation products of 1 at pH 7.0 was isolated by TLC and identified as the aziridine derivative by MS. Investigations were carried out over a range of pH (2.2–10.7) and buffer concentration [ionic strength ( μ ), 0.25–4.18] at 23°C. The degradation followed buffer‐catalyzed, pseudo‐first‐order kinetics and was accelerated by a decrease in pH and an increase in temperature. The activation energy for the degradation in citric acid‐phosphate buffer (pH 7.0 and constant ionic strength μ at 0.54) was 12.5 kcal/mol. General acid catalysis was observed at pH 7.0 in citric acid‐phosphate buffer. The salt effect on the degradation obeyed the modified Debye‐Huckel equation well; however, the observed charge product ( Z A Z B ) value (2.69) deviated highly from the theoretical value (1.0), perhaps because of the high μ values (0.25–4.18) of the solutions used. The stability data will be useful in preformulation studies in the development of a stable, oral dosage form of 1.
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Triazolines xxiii high performance liquid chromatographic assay in rat blood for a novel triazoline anticonvulsant add17014
Journal of Chromatography B: Biomedical Sciences and Applications, 1991Co-Authors: Paul J. Stevenson, M.a. Freeke Hamelijnck, Pankaja K. Kadaba, L.a. DamaniAbstract:A sensitive and specific high-performance liquid chromatographic (HPLC) method for the analysis of 1-(4-chlorophenyl)-5-(4-pyridyl)-Δ2-1,2,3-triazoline (ADD17014, I), a novel anticonvulsant agent, in rat blood is described. Compound I and the internal standard (dipyridamole) were extracted into diethyl ether (5 ml) from alkalinised blood (0.25 ml of blood plus 0.75 ml of pH 10.7 buffer), with extractability nearing 100% under these conditions. The assay is based on reversed-phase HPLC (25 cm × 0.46 cm I.D. Spherisorb 5-ODS) using a mobile phase of methanol—acetonitrile—McIlvaine's citric acid—phosphate buffer (pH 8.0, 0.005 M) (30:30:40, v/v) and ultraviolet detection at 290 nm. Calibration curves were linear and reproducible (correlation coefficient > 0.999). Measurement of I in rat blood (250 μl sample size) was linear in the range 0–40 μg/ml and the coefficient of variation was less than 5%. The minimum detectable level was about 0.1 μg/ml; however, a larger blood sample size (1–2 ml) allowed measurement of levels as low as 10 ng/ml, especially for estimation of drug levels in samples withdrawn at later time points (24 h).
Paul J. Stevenson - One of the best experts on this subject based on the ideXlab platform.
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Triazolines xxvii δ2 1 2 3 triazoline anticonvulsants novel built in heterocyclic prodrugs with a unique dual action mechanism for impairing excitatory amino acid l glutamate neurotransmission
Bioorganic & Medicinal Chemistry, 1996Co-Authors: Pankaja K. Kadaba, Paul J. Stevenson, Ivo Pnnane, L.a. DamaniAbstract:The delta2-1,2,3-triazoline anticonvulsants (1) may be considered as representing a unique class of 'built-in' heterocyclic prodrugs where the active 'structure element' is an integral part of the ring system and can be identified only by a knowledge of their chemical reactivity and metabolism. Investigations on the metabolism and pharmacology of a lead triazoline, ADD17014 (1a), suggest that the Triazolines function as 'prodrugs' and exert their anticonvulsant activity by impairing excitatory amino acid (EAA) L-glutamate (L-Glu) neurotransmission via a unique 'dual-action' mechanism. While an active beta-amino alcohol metabolite, 2a, from the parent prodrug acts as an N-methyl-D-aspartate (NMDA)/MK-801 receptor antagonist, the parent triazoline impairs the presynaptic release of L-Glu. Various pieces of theoretical reasoning and experimental evidence led to the elucidation of the dual-action mechanism. Based on the unique chemistry of the Triazolines, the potential metabolic pathways and biotransformation products of 1a were predicted to be the beta-amino alcohols 2a and 2a', the alpha-amino acid 3a, the triazole 4a, the aziridine 5a, and the ketimine 6a. In vivo and in vitro pharmacological studies of 1a and potential metabolities, along with a full quantitative urinary metabolic profiling of 1a, indicated the beta-amino alcohol 2a as the active species. It was the only compound that inhibited the specific binding of [3H]MK-801 to the MK-801 site, 56% at 10 microM drug concentration, but itself had no anticonvulsant activity, suggesting 1a acted as a prodrug. Three metabolites were identified; 2a was the most predominant, with lesser amounts of 2a', and very minor amounts of aziridine 5a. Since only 5a can yield 2a', its formation indicated that the biotransformation of 1a occurred, at least in part, through 5a. No amino acid metabolite 3a was detected, which implied that no in vivo oxidation of 2a or oxidative biotransformation of 1a or 5a by hydroxylation at the methylene group occurred. While triazoline 1a significantly decreased Ca2(+)-dependent, K(+)-evoked L-Glu release (83% at 100 microM drug concentration), Triazolines 1a-1c showed an augmentation of 50-63%, in the Cl- channel activity, a useful membrane action that reduces the excessive L-Glu release that occurs during epileptic seizures. The high anticonvulsant activity of 1a may be due to its unique dual-action mechanism whereby 1a and 2a together effectively impair both pre- and postsynaptic aspects of EAA neurotransmission, and has clinical potential in complex partial epilepsy which is refractory to currently available drugs.
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Triazolines—XXVII. Δ2-1,2,3-triazoline anticonvulsants: Novel ‘built-in’ heterocyclic prodrugs with a unique ‘dual-action’ mechanism for impairing excitatory amino acid l-glutamate neurotransmission
Bioorganic & medicinal chemistry, 1996Co-Authors: Pankaja K. Kadaba, Paul J. Stevenson, Ivo P-nnane, L.a. DamaniAbstract:The delta2-1,2,3-triazoline anticonvulsants (1) may be considered as representing a unique class of 'built-in' heterocyclic prodrugs where the active 'structure element' is an integral part of the ring system and can be identified only by a knowledge of their chemical reactivity and metabolism. Investigations on the metabolism and pharmacology of a lead triazoline, ADD17014 (1a), suggest that the Triazolines function as 'prodrugs' and exert their anticonvulsant activity by impairing excitatory amino acid (EAA) L-glutamate (L-Glu) neurotransmission via a unique 'dual-action' mechanism. While an active beta-amino alcohol metabolite, 2a, from the parent prodrug acts as an N-methyl-D-aspartate (NMDA)/MK-801 receptor antagonist, the parent triazoline impairs the presynaptic release of L-Glu. Various pieces of theoretical reasoning and experimental evidence led to the elucidation of the dual-action mechanism. Based on the unique chemistry of the Triazolines, the potential metabolic pathways and biotransformation products of 1a were predicted to be the beta-amino alcohols 2a and 2a', the alpha-amino acid 3a, the triazole 4a, the aziridine 5a, and the ketimine 6a. In vivo and in vitro pharmacological studies of 1a and potential metabolities, along with a full quantitative urinary metabolic profiling of 1a, indicated the beta-amino alcohol 2a as the active species. It was the only compound that inhibited the specific binding of [3H]MK-801 to the MK-801 site, 56% at 10 microM drug concentration, but itself had no anticonvulsant activity, suggesting 1a acted as a prodrug. Three metabolites were identified; 2a was the most predominant, with lesser amounts of 2a', and very minor amounts of aziridine 5a. Since only 5a can yield 2a', its formation indicated that the biotransformation of 1a occurred, at least in part, through 5a. No amino acid metabolite 3a was detected, which implied that no in vivo oxidation of 2a or oxidative biotransformation of 1a or 5a by hydroxylation at the methylene group occurred. While triazoline 1a significantly decreased Ca2(+)-dependent, K(+)-evoked L-Glu release (83% at 100 microM drug concentration), Triazolines 1a-1c showed an augmentation of 50-63%, in the Cl- channel activity, a useful membrane action that reduces the excessive L-Glu release that occurs during epileptic seizures. The high anticonvulsant activity of 1a may be due to its unique dual-action mechanism whereby 1a and 2a together effectively impair both pre- and postsynaptic aspects of EAA neurotransmission, and has clinical potential in complex partial epilepsy which is refractory to currently available drugs.
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Triazolines. XXI: Preformulation Degradation Kinetics and Chemical Stability of a Novel Triazoline Anticonvulsant
Journal of Pharmaceutical Sciences, 1992Co-Authors: M.a. Freeke Hamelijnck, Paul J. Stevenson, Pankaja K. Kadaba, L.a. DamaniAbstract:Abstract The effect of pH, temperature, and two buffer species (citric acid‐phosphate and bicarbonate‐carbonate) on the stability of 1‐(4‐chlorophenyl)‐5‐(4‐pyridyl)‐Δ 2 ‐1,2,3‐triazoline (ADD17014; 1), a novel triazoline anticonvulsant, was determined by HPLC. One of the main degradation products of 1 at pH 7.0 was isolated by TLC and identified as the aziridine derivative by MS. Investigations were carried out over a range of pH (2.2–10.7) and buffer concentration [ionic strength ( μ ), 0.25–4.18] at 23°C. The degradation followed buffer‐catalyzed, pseudo‐first‐order kinetics and was accelerated by a decrease in pH and an increase in temperature. The activation energy for the degradation in citric acid‐phosphate buffer (pH 7.0 and constant ionic strength μ at 0.54) was 12.5 kcal/mol. General acid catalysis was observed at pH 7.0 in citric acid‐phosphate buffer. The salt effect on the degradation obeyed the modified Debye‐Huckel equation well; however, the observed charge product ( Z A Z B ) value (2.69) deviated highly from the theoretical value (1.0), perhaps because of the high μ values (0.25–4.18) of the solutions used. The stability data will be useful in preformulation studies in the development of a stable, oral dosage form of 1.
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Triazolines xxiii high performance liquid chromatographic assay in rat blood for a novel triazoline anticonvulsant add17014
Journal of Chromatography B: Biomedical Sciences and Applications, 1991Co-Authors: Paul J. Stevenson, M.a. Freeke Hamelijnck, Pankaja K. Kadaba, L.a. DamaniAbstract:A sensitive and specific high-performance liquid chromatographic (HPLC) method for the analysis of 1-(4-chlorophenyl)-5-(4-pyridyl)-Δ2-1,2,3-triazoline (ADD17014, I), a novel anticonvulsant agent, in rat blood is described. Compound I and the internal standard (dipyridamole) were extracted into diethyl ether (5 ml) from alkalinised blood (0.25 ml of blood plus 0.75 ml of pH 10.7 buffer), with extractability nearing 100% under these conditions. The assay is based on reversed-phase HPLC (25 cm × 0.46 cm I.D. Spherisorb 5-ODS) using a mobile phase of methanol—acetonitrile—McIlvaine's citric acid—phosphate buffer (pH 8.0, 0.005 M) (30:30:40, v/v) and ultraviolet detection at 290 nm. Calibration curves were linear and reproducible (correlation coefficient > 0.999). Measurement of I in rat blood (250 μl sample size) was linear in the range 0–40 μg/ml and the coefficient of variation was less than 5%. The minimum detectable level was about 0.1 μg/ml; however, a larger blood sample size (1–2 ml) allowed measurement of levels as low as 10 ng/ml, especially for estimation of drug levels in samples withdrawn at later time points (24 h).
C. T. Watts - One of the best experts on this subject based on the ideXlab platform.
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Organic Syntheses - 4‐Phenyl‐1,2,4‐Triazoline‐3,5‐Dione
Organic Syntheses, 2003Co-Authors: R. C. Cookson, S. S. Gupte, I. D. R. Stevens, C. T. WattsAbstract:4-Phenyl-1,2,4-triazoline-3,5-dione intermediate: 52 g. (0.50 mole) of ethyl hydrazinecarboxylate in 550 ml. of dry benzene intermediate: 4-phenyl-1-carbethoxysemicarbazide intermediate: 4-phenylurazole product: 4-(4-nitrophenyl)urazole product: 4-tert-butylurazole product: 4-Benzalaminourazole product: 4-benzalamino-1,2,4-triazoline-3,5-dione product: 4-Phenyl-1,2,4-triazoline-3,5-dione Keywords: addition, to NCO; annulation, heterocyclic-[5]; carbonylation; condensation, miscellaneous; cyclization, condensation; oxidation, NH–NH NN; benzene; ethyl acetate
Karl Anker Jørgensen - One of the best experts on this subject based on the ideXlab platform.
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synthesis of 1 2 4 Triazolines base catalyzed hydrazination cyclization cascade of α isocyano esters and amides
Organic Letters, 2011Co-Authors: David Monge, Kim L. Jensen, Irene Marín, Karl Anker JørgensenAbstract:A convenient, efficient synthesis of 1,2,4-Triazolines from α-isocyano esters/amides and azodicarboxylates is presented. The developed reaction cascade is based on a base-catalyzed hydrazination-type reaction followed by a subsequent cyclization providing the Triazolines in good to excellent yields (75-99%). Phosphine-catalyzed and preliminary asymmetric phase-transfer catalysis approaches have also been investigated.
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Synthesis of 1,2,4-Triazolines: base-catalyzed hydrazination/cyclization cascade of α-isocyano esters and amides.
Organic letters, 2010Co-Authors: David Monge, Kim L. Jensen, Irene Marín, Karl Anker JørgensenAbstract:A convenient, efficient synthesis of 1,2,4-Triazolines from α-isocyano esters/amides and azodicarboxylates is presented. The developed reaction cascade is based on a base-catalyzed hydrazination-type reaction followed by a subsequent cyclization providing the Triazolines in good to excellent yields (75-99%). Phosphine-catalyzed and preliminary asymmetric phase-transfer catalysis approaches have also been investigated.
