Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 8 de 8
Filter
Add more filters










Database
Language
Publication year range
1.
J Med Chem ; 64(8): 5157-5170, 2021 04 22.
Article in English | MEDLINE | ID: mdl-33826322

ABSTRACT

The synthesis and pharmacological activity of a new series of 5a,7,8,8a-tetrahydro-4H,6H-pyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine derivatives as potent sigma-1 receptor (σ1R) ligands are reported. A lead optimization program aimed at improving the aqueous solubility of parent racemic nonpolar derivatives led to the identification of several σ1R antagonists with a good absorption, distribution, metabolism, and excretion in vitro profile, no off-target affinities, and characterized by a low basic pKa (around 5) that correlates with high exposure levels in rodents. Two compounds displaying a differential brain-to-plasma ratio distribution profile, 12lR and 12qS, exhibited a good analgesic profile and were selected as preclinical candidates for the treatment of pain.


Subject(s)
Analgesics/chemistry , Receptors, sigma/antagonists & inhibitors , Triazoles/chemistry , Analgesics/metabolism , Analgesics/pharmacology , Analgesics/therapeutic use , Animals , Cell Membrane Permeability/drug effects , Disease Models, Animal , Female , Half-Life , Humans , Ligands , Male , Mice , Microsomes, Liver/metabolism , Pain/drug therapy , Rats , Rats, Wistar , Receptors, sigma/metabolism , Structure-Activity Relationship , Triazoles/metabolism , Triazoles/pharmacology , Triazoles/therapeutic use , Sigma-1 Receptor
2.
J Med Chem ; 64(4): 2167-2185, 2021 02 25.
Article in English | MEDLINE | ID: mdl-33591743

ABSTRACT

The synthesis and pharmacological activity of a new series of bicyclic diazepinones with dual activity toward the α2δ-1 subunit of voltage-gated calcium channels (Cavα2δ-1) and the norepinephrine transporter (NET) are reported. Exploration of the positions amenable for substitution on a nonaminoacidic Cavα2δ-1 scaffold allowed the identification of favorable positions for the attachment of NET pharmacophores. Among the patterns explored, attachment of the 2-ethylamino-9-methyl-6-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin-5-one framework to the meta-position of the phenyl ring of the 3-methylamino-1-phenylpropoxy and 3-methylamino-1-thiophenylpropoxy moieties provided dual compounds with excellent NET functionality. Alternative bicyclic frameworks were also explored, and some lead molecules were identified, which showed a balanced dual profile and exhibited good ADMET properties.


Subject(s)
Azepines/pharmacology , Calcium Channels/metabolism , Heterocyclic Compounds, 2-Ring/pharmacology , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Animals , Azepines/chemical synthesis , Azepines/metabolism , CHO Cells , Cricetulus , HEK293 Cells , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/metabolism , Humans , Ligands , Molecular Docking Simulation , Molecular Structure , Protein Binding , Structure-Activity Relationship
3.
Chemistry ; 17(32): 8780-3, 2011 Aug 01.
Article in English | MEDLINE | ID: mdl-21735502

ABSTRACT

Lighten the load! A family of enantiopure 4-oxy-substituted 3-aminopyrrolidines arising from the enantioselective ring-opening of meso-3-pyrroline oxide have been developed as catalysts for the asymmetric, anti-selective Mannich reaction (see scheme; PMP=p-methoxyphenyl; PG=protecting group). Very high catalytic activity (down to 0.01 mol % loading) and stereoselectivity have been recorded.


Subject(s)
Aldehydes/chemistry , Imines/chemistry , Ketones/chemistry , Pyrrolidines/chemistry , Amines/chemical synthesis , Amines/chemistry , Catalysis , Ketones/chemical synthesis , Molecular Structure , Stereoisomerism
4.
Org Lett ; 10(8): 1617-9, 2008 Apr 17.
Article in English | MEDLINE | ID: mdl-18348569

ABSTRACT

The synthesis of novel tricyclic 1,2,3-triazoles starting from cyclic epoxides via the sequential azidolysis, propargylation and 1,3-dipolar cycloaddition is described. Derivatization by N-arylation reaction and the synthesis of enantiomerically pure compounds is also reported. Some of these compounds exhibit significant affinity for the sigma-1 receptor.

5.
Org Lett ; 7(24): 5485-7, 2005 Nov 24.
Article in English | MEDLINE | ID: mdl-16288537

ABSTRACT

[structure: see text] Two flexible receptors for carboxylic acids, based on 1-amino-3-fluoro-2-alcohol functional arrays and built on aminomethylpyridine platforms, are described. The C(2)-symmetric one [from 2,6-bis(aminomethyl)pyridine] has been shown to be an efficient CSA due to its ability to form geometrically different diastereomeric complexes enabling the discrimination between the enantiomers of a series of carboxylic acid in the (1)H NMR spectra.

6.
Org Biomol Chem ; 3(5): 764-86, 2005 Mar 07.
Article in English | MEDLINE | ID: mdl-15731862

ABSTRACT

The binding modes of a series of molecules, containing the glucosamine (1-->6) myo-inositol structural motif, into the ATP binding site of the catalytic subunit of cAMP-dependent protein kinase (PKA) have been analysed using molecular docking. These calculations predict that the presence of a phosphate group at the non-reducing end in pseudodisaccharide and pseudotrisaccharide structures properly orientate the molecule into the binding site and that pseudotrisaccharide structures present the best shape complementarity. Therefore, pseudodisaccharides and pseudotrisaccharides have been synthesised from common intermediates using effective synthetic strategies. On the basis of this synthetic chemistry, the feasibility of constructing small pseudotrisaccharide libraries on solid-phase using the same intermediates has been explored. The results from the biological evaluation of these molecules provide additional support to an insulin-mediated signalling system which involves the intermediacy of inositolphosphoglycans as putative insulin mediators.


Subject(s)
Drug Design , Inositol Phosphates/chemical synthesis , Insulin/metabolism , Polysaccharides/chemical synthesis , Adenosine Triphosphate/chemistry , Adenosine Triphosphate/metabolism , Animals , Binding Sites , Computer Simulation , Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Cyclic AMP-Dependent Protein Kinases/metabolism , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/metabolism , Hypoglycemic Agents/pharmacology , Inositol Phosphates/metabolism , Inositol Phosphates/pharmacology , Models, Molecular , Molecular Mimicry , Molecular Structure , Oligosaccharides/chemical synthesis , Oligosaccharides/metabolism , Oligosaccharides/pharmacology , Polysaccharides/metabolism , Polysaccharides/pharmacology , Protein Binding , Pyruvate Dehydrogenase (Lipoamide)-Phosphatase/chemistry , Signal Transduction/drug effects
7.
J Med Chem ; 47(23): 5700-12, 2004 Nov 04.
Article in English | MEDLINE | ID: mdl-15509169

ABSTRACT

With the aim of studying the contribution of the beta II turn conformation at the side chain of didemnins to the bioactive conformation responsible for their antitumoral activity, conformationally restricted analogues of aplidine and tamandarin A, where the side chain dipeptide Pro8-N-Me-d-Leu7 is replaced with the spirolactam beta II turn mimetic (5R)-7-[(1R)-1-carbonyl-3-methylbutyl]-6-oxo-1,7-diazaspiro[4.4]nonane, were prepared. Additionally, restricted analogues, where the aplidine (pyruvyl9) or tamandarin A [(S)-Lac9] acyl groups are replaced with the isobutyryl, Boc, and 2-methylacryloyl groups, were also prepared. These structural modifications were detrimental to cytotoxic activity, leading to a decrease of 1-2 orders of magnitude with respect to that exhibited by aplidine and tamandarin A. The conformational analysis of one of these spirolactam aplidine analogues, by NMR and molecular modeling methods, showed that the conformational restriction caused by the spirolactam does not produce significant changes in the overall conformation of aplidine, apart from preferentially stabilizing the trans rotamer at the pyruvyl9-spirolactam amide bond, whereas in aplidine both cis and trans rotamers at the pyruvyl9-Pro8 amide bond are more or less equally stabilized. These results seem to indicate a preference for the cis form at that amide bond in the bioactive conformation of aplidine. The significant influence of this cis/trans isomerism upon the cytotoxicity suggests a possible participation of a peptidylprolyl cis/trans isomerase in the mechanism of action of aplidine.


Subject(s)
Antineoplastic Agents/chemical synthesis , Depsipeptides/chemical synthesis , Lactams/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Depsipeptides/chemistry , Depsipeptides/pharmacology , Drug Screening Assays, Antitumor , Humans , Lactams/chemistry , Lactams/pharmacology , Magnetic Resonance Spectroscopy , Models, Molecular , Peptides, Cyclic , Protein Structure, Secondary , Structure-Activity Relationship
8.
Angew Chem Int Ed Engl ; 37(11): 1534-1537, 1998 Jun 19.
Article in English | MEDLINE | ID: mdl-29710935

ABSTRACT

One order of magnitude: The transport of Na+ and K+ ions through a phospholipid bilayer occurs with much higher conductance levels with 1 and 2 than with typical Na+ -transporting proteins or gramicidin. However, the cations do not appear to pass through the calix[4]arene ring, which has a rigid 1,3-alternate conformation. diazacrown=10-benyzl-1,10-diaza[18]crown-6 group.

SELECTION OF CITATIONS
SEARCH DETAIL
...