The low affinity metabotropic glutamate receptor mGluR7 has been implicated in numerous CNS disorders; however, a paucity of potent and selective activators has hampered full delineation of the ...functional role and therapeutic potential of this receptor. In this work, we present the identification, optimization, and characterization of highly potent, novel mGluR7 agonists. Of particular interest is the chromane CVN636, a potent (EC50 7 nM) allosteric agonist which demonstrates exquisite selectivity for mGluR7 compared to not only other mGluRs, but also a broad range of targets. CVN636 demonstrated CNS penetrance and efficacy in an in vivo rodent model of alcohol use disorder. CVN636 thus has potential to progress as a drug candidate in CNS disorders involving mGluR7 and glutamatergic dysfunction.
The low affinity metabotropic glutamate receptor mGluR
has been implicated in numerous CNS disorders; however, a paucity of potent and selective activators has hampered full delineation of the ...functional role and therapeutic potential of this receptor. In this work, we present the identification, optimization, and characterization of highly potent, novel mGluR
agonists. Of particular interest is the chromane
, a potent (EC
7 nM) allosteric agonist which demonstrates exquisite selectivity for mGluR
compared to not only other mGluRs, but also a broad range of targets.
demonstrated CNS penetrance and efficacy in an
rodent model of alcohol use disorder.
thus has potential to progress as a drug candidate in CNS disorders involving mGluR
and glutamatergic dysfunction.
Structural modifications to the peptide deformylase inhibitor BB-3497 are described. In this paper, we describe the initial SAR around this lead for modifications to the methylene spacer and the P1′ ...side chain. Enzyme inhibition and antibacterial activity data revealed that the optimum distance between the
N-formyl hydroxylamine metal binding group and the P1′ side chain is one unsubstituted methylene unit. Additionally, lipophilic P1′ side chains that closely mimic the methionine residue in the substrate provided compounds with the best microbiological profile.
Structural modifications to the peptide deformylase inhibitor BB-3497 are described
Structural modifications to the peptide deformylase inhibitor BB-3497 are described. In this paper, we describe the initial SAR around this lead for modifications to both the P2′ and P3′ side chains. ...Enzyme inhibition and antibacterial activity data revealed that a variety of substituents are tolerated at the P2′ and P3′ positions of the inhibitor backbone. The data from this study highlights the potential for modification at the P2′ and P3′ positions to optimise the physicochemical properties.
Structural modifications to the peptide deformylase inhibitor BB-3497 are described, highlighting the initial SAR around this lead for modifications to both the P2′ and P3′ side chains.
The presence of the quinazolin-4(3H)-one ring (Q
∗) in
N-(Q
∗)-aziridines facilitates ring-opening by nucleophiles: removal of the Q
∗ group from enantiopure ring-opened products gives useful ...chirons.
Graphic
The specific rotation of (
R
Fe,
R,
M)-
4
switches sign upon epimerisation to (
R
Fe,
S,
P)-
5. X-Ray crystallographic studies suggest that inversion of the propeller configuration of the coordinated ...PPh
3 ligand is a major contributor to the switch of specific rotation. A simple model for predicting the conformational diastereoisomeric forms of PPh
3 is presented, suggesting future routes towards the design of molecular optical switching devices.
The specific rotation of (
R
Fe,
R,
M)-
4
switches sign upon epimerisation to (
R
Fe,
S,
P)-
5. X-Ray crystallographic studies suggest that inversion of the propeller configuration of the coordinated PPh
3 ligand is the major contributor to the switch of specific rotation.
The presence of the quinazolin-4(3H)-one (Q) ring in 1-(Q)-2-vinylaziridine (
2) can be used to control the stereochemistry of the 3-membered ring-opening; participation by the quinazolinone carbonyl ...oxygen brings about ring-opening with retention of configuration.
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A series of N-formyl hydroxylamine peptide deformylase inhibitors containing a cyclic azaamino acid moiety between the P1′ and P3′ substituents are presented. Selected compounds display antibacterial ...activity against pathogens associated with respiratory tract infections with representative compounds showing excellent MICs against Haemophilus influenzae.
