High-throughput screening of 3.87 million compounds delivered a novel series of non-steroidal GR antagonists. Subsequent rounds of optimisation allowed progression from a non-selective ligand with a poor ADMET profile to an orally bioavailable, selective, stable, glucocorticoid receptor antagonist.
Receptors, Glucocorticoid/antagonists & inhibitors , Animals , Drug Evaluation, Preclinical , High-Throughput Screening Assays , Humans , Hydrocortisone/chemistry , Microsomes/metabolism , Rats , Receptors, Glucocorticoid/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics
Excitatory Amino Acid Agents/chemistry , Receptors, AMPA/physiology , Allosteric Regulation , Animals , Benzamides/chemistry , Benzamides/pharmacology , Benzothiadiazines/chemistry , Benzothiadiazines/pharmacology , Binding Sites , Excitatory Amino Acid Agents/pharmacology , Humans , Indazoles/chemistry , Indazoles/pharmacology , Ligands , Models, Molecular , Protein Conformation , Receptors, AMPA/chemistry , Sulfonamides/chemistry , Sulfonamides/pharmacology
The synthesis of the complete family of phosphatidylinositol phosphate analogues (PIPs) from five key core intermediates A-E is described. These core compounds were obtained from myo-inositol orthoformate 1 via regioselective DIBAL-H and trimethylaluminium-mediated cleavages and a resolution-protection process using camphor acetals 10. Coupling of cores A-E with phosphoramidites 34 and 38, derived from the requisite protected lipid side chains, afforded the fully-protected PIPs. Removal of the remaining protecting groups was achieved via hydrogenolysis using palladium black or palladium hydroxide on carbon in the presence of sodium bicarbonate to afford the complete family of dipalmitoyl- and amino-PIP analogues 42, 45, 50, 51, 58, 59, 67, 68, 76, 77, 82, 83, 92, 93, 99 and 100. Investigations using affinity probes incorporating these compounds have identified novel proteins involved in the PI3K intracellular signalling network and have allowed a comprehensive proteomic analysis of phosphoinositide interacting proteins.
Phosphatidylinositol Phosphates/chemical synthesis , Phosphatidylinositol Phosphates/metabolism , Cell Line, Tumor , Colonic Neoplasms/metabolism , Humans , Liposomes , Models, Molecular , Organophosphorus Compounds/chemical synthesis , Organophosphorus Compounds/chemistry , Phosphatidylinositol Phosphates/chemistry , Protein Binding , Proteins/isolation & purification , Proteins/metabolism
A series of 3-phenoxypropyl piperidine analogues have been discovered as novel ORL1 receptor agonists. Structure-activity relationships have been explored around the 3-phenoxypropyl region with several potent and selective analogues identified.
Piperidines/chemical synthesis , Piperidines/pharmacology , Receptors, Opioid/agonists , Animals , CHO Cells , Cricetinae , Cyclic AMP/biosynthesis , Drug Design , Humans , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Male , Mice , Structure-Activity Relationship , Transfection , Vas Deferens , Nociceptin Receptor
A series of secondary face modified cyclodextrins (CDs) were synthesised with the aim of constructing host molecules capable of forming host-guest complexes with neuromuscular blockers, especially with rocuronium bromide. Perfacial 2-O-substitution of gamma-CD with 4-carboxybenzyl resulted in a CD host molecule 1 that forms a 1:1 binary complex with rocuronium bromide (K(a) 6.2 x 10(5) M(-1)). The biological activities of this compound and other derivatives as reversal agents of rocuronium bromide were examined in vitro (mouse hemi-diaphragm) and in vivo (anaesthetized guinea pigs). The host molecule 1 was found to exert potent reversal activity (ED(50) 0.21 micromol/kg, iv) against rocuronium-induced neuromuscular block, and thus proved the viability of using host molecules as antidotes of a biologically active compound.
Androstanols/antagonists & inhibitors , Cyclodextrins/chemical synthesis , Cyclodextrins/pharmacology , Neuromuscular Nondepolarizing Agents/antagonists & inhibitors , Androstanols/pharmacology , Animals , Cyclodextrins/chemistry , Diaphragm/drug effects , Diaphragm/physiology , Guinea Pigs , In Vitro Techniques , Male , Mice , Molecular Structure , Muscle Relaxation/drug effects , Neuromuscular Blockade , Neuromuscular Nondepolarizing Agents/pharmacology , Rocuronium , Structure-Activity Relationship
A series of oxyanilinium-based AChE inhibitors have been synthesised and tested for the reversal of vecuronium-induced neuromuscular block. Several compounds, for example 2-hydroxy- and 2-methoxy-N,N-dimethyl-N-allylanilinium bromide (3 and 6) showed comparable reversal potencies to edrophonium and clean in vivo cardiovascular profiles.
Acetylcholinesterase/drug effects , Allyl Compounds/pharmacology , Aniline Compounds/pharmacology , Cholinesterase Inhibitors/pharmacology , Edrophonium/antagonists & inhibitors , Neuromuscular Blocking Agents/antagonists & inhibitors , Allyl Compounds/chemistry , Aniline Compounds/chemistry , Crystallography, X-Ray , Structure-Activity Relationship
