1727-09-9Relevant academic research and scientific papers
N-benzyl residues as the P10 substituents in phosphorus-containing extended transition state analog inhibitors of metalloaminopeptidases
Janiszewska, Kamila,Kafarski, Pawe?,Mucha, Artur,Oszywa, Bartosz,Pawe?czak, Ma?gorzata,Talma, Micha?
, (2020)
Peptidyl enzyme inhibitors containing an internal aminomethylphosphinic bond system (P(O)(OH)-CH2-NH) can be termed extended transition state analogs by similarity to the corresponding phosphonamidates (P(O)(OH)-NH). Phosphonamidate pseudopeptides are broadly recognized as competitive mechanism-based inhibitors of metalloenzymes, mainly hydrolases. Their practical use is, however, limited by hydrolytic instability, which is particularly restricting for dipeptide analogs. Extension of phosphonamidates by addition of the methylene group produces a P-C-N system fully resistant in water conditions. In the current work, we present a versatile synthetic approach to such modified dipeptides, based on the three-component phospha-Mannich condensation of phosphinic acids, formaldehyde, and N-benzylglycines. The last-mentioned component allowed for simple and versatile introduction of functionalized P10 residues located on the tertiary amino group. The products demonstrated moderate inhibitory activity towards porcine and plant metalloaminopeptidases, while selected derivatives appeared very potent with human alanyl aminopeptidase (Ki = 102 nM for 6a). Analysis of ligand-protein complexes obtained by molecular modelling revealed canonical modes of interactions for mono-metallic alanyl aminopeptidases, and distorted modes for di-metallic leucine aminopeptidases (with C-terminal carboxylate, not phosphinate, involved in metal coordination). In general, the method can be dedicated to examine P10-S10 complementarity in searching for non-evident structures of specific residues as the key fragments of perspective ligands.
Structure-kinetic relationship studies of cannabinoid CB2 receptor agonists reveal substituent-specific lipophilic effects on residence time
Soethoudt, Marjolein,Hoorens, Mark W.H.,Doelman, Ward,Martella, Andrea,van der Stelt, Mario,Heitman, Laura H.
, p. 129 - 142 (2018/11/23)
A decade ago, the drug-target residence time model has been (re-)introduced, which describes the importance of binding kinetics of ligands on their protein targets. Since then, it has been applied successfully for multiple protein targets, including GPCRs, for the development of lead compounds with slow dissociation kinetics (i.e. long target residence time) to increase in vivo efficacy or with short residence time to prevent on-target associated side effects. To date, this model has not been applied in the design and pharmacological evaluation of novel selective ligands for the cannabinoid CB2 receptor (CB2R), a GPCR with therapeutic potential in the treatment of tissue injury and inflammatory diseases. Here, we have investigated the relationships between physicochemical properties, binding kinetics and functional activity in two different signal transduction pathways, G protein activation and β-arrestin recruitment. We synthesized 24 analogues of 3-cyclopropyl-1-(4-(6-((1,1-dioxidothiomorpholino)methyl)-5-fluoropyridin-2-yl)benzyl)imidazoleidine-2,4-dione (LEI101), our previously reported in vivo active and CB2R-selective agonist, with varying basicity and lipophilicity. We identified a positive correlation between target residence time and functional potency due to an increase in lipophilicity on the alkyl substituents, which was not the case for the amine substituents. Basicity of the agonists did not show a relationship with affinity, residence time or functional activity. Our findings provide important insights about the effects of physicochemical properties of the specific substituents of this scaffold on the binding kinetics of agonists and their CB2R pharmacology. This work therefore shows how CB2R agonists can be designed to have optimal kinetic profiles, which could aid the lead optimization process in drug discovery for the study or treatment of inflammatory diseases.
Discovery and optimization of 1-(4-(Pyridin-2-yl)benzyl)imidazolidine-2,4- dione derivatives as a novel class of selective cannabinoid CB2 receptor agonists
Van Der Stelt, Mario,Cals, Jos,Broeders-Josten, Silvia,Cottney, Jean,Van Der Doelen, Antoon A.,Hermkens, Marcel,De Kimpe, Vera,King, Angela,Klomp, Jan,Oosterom, Julia,Pols-De Rooij, Ilse,De Roos, Jeroen,Van Tilborg, Martin,Boyce, Susan,Baker, James
experimental part, p. 7350 - 7362 (2011/12/04)
Here, we report the identification and optimization of 1-(4-(pyridin-2-yl) benzyl)imidazolidine-2,4-dione derivatives as a novel chemotype with selective cannabinoid CB2 receptor agonist activity. 1 is a potent and selective cannabinoid CB2 receptor agonist (hCB2 pEC50 = 8.6). The compound was found to be metabolically unstable, which resulted in low oral bioavailability in rat (Fpo = 4%) and possessed off-target activity at the hERG ion channel (pKi = 5.5). Systematic modification of physicochemical properties, such as lipophilicity and basicity, was used to optimize the pharmacokinetic profile and hERG affinity of this novel class of cannabinoid CB2 receptor agonists. This led to the identification of 44 as a potent, selective, and orally bioavailable cannabinoid CB2 receptor agonist (hCB2 pEC50 = 8.0; hERG pKi po = 100%), which was active in a rat spinal nerve ligation model of neuropathic pain.
HETEROCYCLIC DERIVATIVES
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Page/Page column 45, (2011/05/11)
The present invention relates to a heterocyclic derivative of formula (I) wherein the variables are as defined in the specification, or to a pharmaceutically acceptable salt or solvate thereof. The present invention further relates to pharmaceutical compositions comprising said heterocyclic derivatives and to their use in therapy, for instance in the treatment or prevention of disorders mediated by glutamate dysfunction, such as schizophrenia and generalised anxiety disorder.
1-(BIPHENYL-4-YLMETHYL)IMIDAZOLIDINE-2,4-DIONE
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Page/Page column 12-13, (2010/06/19)
The invention relates to A 1-(biphenyl-4-ylmethyl)imidazolidine-2,4-dione derivative having the general Formula I wherein R1 is H, (C1-6)alkyl (optionally substituted with oxo, OR4, COOR5, halogen or CN), (C2-6)alkenyl, (C2-6)alkynyl, (C3-6)cycloalkyl or (C3-6)cycloalkyl(C1-3)alkyl; R2 and R2′ are independently H or (C1-3)alkyl; or R2 and R2′ form together with the carbon atom to which they are bound a (C3-5)cycloalkyl group; R3 represents H or 1 to 4 F substituents; Y represents or NR8R9; X represents CHR6, CF2, O, S, SO or SO2; R4 and R5 are (C1-6)alkyl; R6 is H, OR7 or CN; R7 is (C1-3)alkyl; R8 is (C5-7)cycloalkyl comprising a heteroatom selected from O, S, SO and SO2; R9 is H or (C1-4)alkyl; o and m represent the ortho or meta position of the substituent Y—CH2; or a pharmaceutically acceptable salt thereof; as well as to the use of said 1-(biphenyl-4-ylmethyl)imidazolidine-2,4-dione derivatives in the treatment of pain such as for example peri-operative pain, chronic pain, neuropathic pain, cancer pain and pain and spasticity associated with multiple sclerosis.
1-(4-(PYRIDIN-2-YL)BENZYL)IMIDAZOLIDINE-2,4-DIONE DERIVATIVES
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Page/Page column 8, (2010/06/19)
The invention relates to 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative having the general Formula I wherein R1 is H, (C1-6)alkyl (optionally substituted with oxo, (C1-3)alkyloxy, (C1-3)alkyloxycar
