AlsoTapered
Bluelighter
- Joined
- Apr 1, 2023
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Some years ago I looked at the work of Professor James T. Cook (UMN) and his work (with at elucidating the a subtypes of the GABA receptor. A number of papers and patents were issued for midazolam derivatives which had an ethyl ester at the 3 position.
US7235656B2 'Anxiolytic agents with reduced sedative and ataxic effects' was the first but PubChem will link to all.
Now, as far as I know Professor Cook (et all) are firmly from the rational design era of drug discovery and an ethyl ester isn't an obvious choice. But then I recognized that the same imidizo ring with the same ester was found in the ultra-short acting hypnotic, etodamate. Etodamate is structurally simple, the only other substitution being a 1-methylbenzyl substituent (Imidazole rings existing as tautomers so covalent bonding isn't aproblem).
Now what I found interesting is that methyl group is chiral and overlays the chiral 3-methyl group found in some benzodiazepines (meclonazepam being an example that's easy to locate) and the benzene ring itself quite closely overlays the pendent aromatic of the 1,4-benzodiazepines.
Now, obviously my next step was to see if etodamate derivatives with ortho substitution of the ring has been explored but alas no. But examples of benzodiazepines with para substitutions are known and are selective to peripheral GABA sites. Lo and behold pCl-fluoroetodamate WAS synthesized and indeed has a CAS number suggesting that someone had at least for a time considered it an area worthy of investment.
It turned out that quite a lot of work had gone into testing various ring-substituted etodamate derivatives:
www.ncbi.nlm.nih.gov
Now, Cook et all replaced the ethyl ester with bioisosteres that were much less liable to metabolism (a 1,2,4-oxadiazole ring OR a 1,2-oxazole) BUT he kept them which infers that they do represent part of the pharmacophore. From his choice it appears that it's the :O:s that are key to affinity)
But it has to be said that etodimate hardly looks like a compound someone would take for fun. but in the original literature it's noted that the chiral methyl is also a key moiety with the (S) enantiomer being some ten times less active (at the α+ – β−/γ+ – β− sites).
But Cook did produce a number of chiral benzodiazepines (the 3-methyl being the chiral centre).
WO-2006004945-A1 'Stereospecific anxiolytic and anticonvulsant agents with reduced muscle-relaxant, sedative-hypnotic and ataxic effects'
US-7618958-B2 'Stereospecific anxiolytic and anticonvulsant agents with reduced muscle-relaxant, sedative-hypnotic and ataxic effects'
The upper reference is to the (S) enantiomer, the lower the (R). I find it quite interesting that two benzodiazepines differing only in the stereochemistry of a 3-methyl substituent should find themselves in different papers. But the question is - what differences does that chiral methyl group make? Presuming replacing the ester with stable ring system overcomes the issue of duration (which the patents suggest they do). The examples with a 1,2-oxazole seem to produce significantly different effects to those with a 1,2,4-oxadiazole (i.e. one of the two
is removed).
I freely admit that it requires quite a deep dive but I do know that Cook et al produced an extremely large set of ligands and through that was able to model many of the benzodiazepine sites of the GABA receptor.
It's going to take rather a long time to find all of those papers again. Cook spent about two decades on the topic working with a Chinese team (QH-II-66 being the work of his Chinese cohort).
I'm going to spend a while reading through some of his work but it would be interesting to find it a fragment of the benzodiazepine scaffold proves to be active. Obviously LogP is going to be an issue given the low MW but it was interesting to note the overlay. It should be remembered that while ortho substitution influences the activity of the 1,4-benzodiazepines, it appears that it offers no useful changes in the 1,5-benzodiazepines or indeed in the closely related benzooxazole class (etifoxine and related compounds),
In the meantime, obviously I DID check if their was much data on (S) etomidate and although their isn't much, what their is suggests that in animal models it significantly increased seizure thresholds Now, whatever else, it does strongly suggest that the two isomers do produce significantly different effects.
It's not possible to rule out ortho substitution of the benzene doesn't alter the effects of the compound, merely that nobody has pursued the matter (or at least PubChem isn't aware of it).
It would be nice to explore this class as I feel quite sure that neither the CSA laws of the US note the Markush definitions used in some other nations would cover such derivatives.
US7235656B2 'Anxiolytic agents with reduced sedative and ataxic effects' was the first but PubChem will link to all.
Now, as far as I know Professor Cook (et all) are firmly from the rational design era of drug discovery and an ethyl ester isn't an obvious choice. But then I recognized that the same imidizo ring with the same ester was found in the ultra-short acting hypnotic, etodamate. Etodamate is structurally simple, the only other substitution being a 1-methylbenzyl substituent (Imidazole rings existing as tautomers so covalent bonding isn't aproblem).
Now what I found interesting is that methyl group is chiral and overlays the chiral 3-methyl group found in some benzodiazepines (meclonazepam being an example that's easy to locate) and the benzene ring itself quite closely overlays the pendent aromatic of the 1,4-benzodiazepines.
Now, obviously my next step was to see if etodamate derivatives with ortho substitution of the ring has been explored but alas no. But examples of benzodiazepines with para substitutions are known and are selective to peripheral GABA sites. Lo and behold pCl-fluoroetodamate WAS synthesized and indeed has a CAS number suggesting that someone had at least for a time considered it an area worthy of investment.
It turned out that quite a lot of work had gone into testing various ring-substituted etodamate derivatives:
Etomidate and Etomidate Analog Binding and Positive Modulation of γ-Aminobutyric Acid Type A Receptors: Evidence for a State-dependent Cutoff Effect
Naphthalene-etomidate, an etomidate analog containing a bulky phenyl ring substituent group, possesses very low γ-aminobutyric acid type A (GABA[A] ) receptor efficacy and acts as an anesthetic-selective competitive antagonist. Using etomidate ...
www.ncbi.nlm.nih.gov
Now, Cook et all replaced the ethyl ester with bioisosteres that were much less liable to metabolism (a 1,2,4-oxadiazole ring OR a 1,2-oxazole) BUT he kept them which infers that they do represent part of the pharmacophore. From his choice it appears that it's the :O:s that are key to affinity)
But it has to be said that etodimate hardly looks like a compound someone would take for fun. but in the original literature it's noted that the chiral methyl is also a key moiety with the (S) enantiomer being some ten times less active (at the α+ – β−/γ+ – β− sites).
But Cook did produce a number of chiral benzodiazepines (the 3-methyl being the chiral centre).
WO-2006004945-A1 'Stereospecific anxiolytic and anticonvulsant agents with reduced muscle-relaxant, sedative-hypnotic and ataxic effects'
US-7618958-B2 'Stereospecific anxiolytic and anticonvulsant agents with reduced muscle-relaxant, sedative-hypnotic and ataxic effects'
The upper reference is to the (S) enantiomer, the lower the (R). I find it quite interesting that two benzodiazepines differing only in the stereochemistry of a 3-methyl substituent should find themselves in different papers. But the question is - what differences does that chiral methyl group make? Presuming replacing the ester with stable ring system overcomes the issue of duration (which the patents suggest they do). The examples with a 1,2-oxazole seem to produce significantly different effects to those with a 1,2,4-oxadiazole (i.e. one of the two
is removed).I freely admit that it requires quite a deep dive but I do know that Cook et al produced an extremely large set of ligands and through that was able to model many of the benzodiazepine sites of the GABA receptor.
It's going to take rather a long time to find all of those papers again. Cook spent about two decades on the topic working with a Chinese team (QH-II-66 being the work of his Chinese cohort).
I'm going to spend a while reading through some of his work but it would be interesting to find it a fragment of the benzodiazepine scaffold proves to be active. Obviously LogP is going to be an issue given the low MW but it was interesting to note the overlay. It should be remembered that while ortho substitution influences the activity of the 1,4-benzodiazepines, it appears that it offers no useful changes in the 1,5-benzodiazepines or indeed in the closely related benzooxazole class (etifoxine and related compounds),
In the meantime, obviously I DID check if their was much data on (S) etomidate and although their isn't much, what their is suggests that in animal models it significantly increased seizure thresholds Now, whatever else, it does strongly suggest that the two isomers do produce significantly different effects.
It's not possible to rule out ortho substitution of the benzene doesn't alter the effects of the compound, merely that nobody has pursued the matter (or at least PubChem isn't aware of it).
It would be nice to explore this class as I feel quite sure that neither the CSA laws of the US note the Markush definitions used in some other nations would cover such derivatives.