ABSTRACT
A new series of 2-(benzyloxy)benzamides are presented that are potent functional antagonists of TRPM8 and possess improved LipE and LE compared to the original lead. They were discovered through a series of compound libraries and we present a powerful visualization method for the chemical space explored with each library. Remarkably this new series originated from the highest risk design strategy where compounds were synthesised with the least degree of similarity to the lead structure.
Subject(s)
Benzamides/pharmacology , TRPM Cation Channels/antagonists & inhibitors , Animals , Drug Design , Drug Discovery , Humans , Rats , Structure-Activity RelationshipABSTRACT
A series of p-hydroxybenzenesulphonamides ERß receptor agonists were discovered and several compounds identified had excellent selectivity over the related ERα receptor. One of these, compound 11, had an interesting binding conformation determined by X-ray and represents an excellent starting point in the quest for further selective ERß agonists.
Subject(s)
Drug Discovery , Estrogen Receptor beta/agonists , Sulfonamides/chemistry , Sulfonamides/pharmacology , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/genetics , Estrogen Receptor beta/metabolism , Female , Humans , Ligands , Models, Chemical , Protein Binding , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/metabolismABSTRACT
A second wave of potential SSRIs with high ease of synthetic accessibility were designed based on the reported selective serotonin re-uptake inhibitor litoxetine and our own previous work in this area. Preparation and subsequent optimisation yielded a range of potent and highly selective SSRIs.
Subject(s)
Antidepressive Agents/chemistry , Selective Serotonin Reuptake Inhibitors/chemistry , Serotonin Plasma Membrane Transport Proteins/chemistry , Adrenergic Uptake Inhibitors/chemistry , Adrenergic Uptake Inhibitors/pharmacology , Antidepressive Agents/chemical synthesis , Antidepressive Agents/pharmacology , Dopamine Uptake Inhibitors/chemistry , Dopamine Uptake Inhibitors/pharmacology , Drug Design , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
The reported selective serotonin Re-uptake Inhibitor Litoxetine was used as the starting point in the design of a range of potential SSRIs with high ease of synthetic accessibility. Preparation and subsequent optimization yielded a range of potent and highly selective SSRIs.
Subject(s)
Drug Design , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Cell Line , Humans , Piperidines/chemical synthesis , Piperidines/metabolism , Selective Serotonin Reuptake Inhibitors/metabolism , Structure-Activity RelationshipABSTRACT
A series of thio-alkyl containing diphenylethers were designed and evaluated, as a strategy to competitively direct metabolism away from unwanted amine N-demethylation and deliver a pharmacologically inactive S-oxide metabolite. Overall, sulfonamide 20 was found to possess the best balance of target pharmacology, pharmacokinetics and metabolism profile.
Subject(s)
Benzylamines/chemical synthesis , Benzylamines/pharmacology , Phenyl Ethers/chemical synthesis , Phenyl Ethers/pharmacology , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacology , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Benzylamines/chemistry , Combinatorial Chemistry Techniques , Humans , Molecular Structure , Phenyl Ethers/chemistry , Selective Serotonin Reuptake Inhibitors/chemistry , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
A series of substituted benzylamines 2-48 were prepared as part of a strategy to identify structurally differentiated and synthetically more accessible selective serotonin reuptake inhibitors, relative to clinical candidate 1. In particular, 44 and 48; demonstrated low nanomolar potency and good selectivity, in a structurally simplified template and, in vivo, very low Vdu, significantly lower than l, and a more rapid T(max), consistent with our clinical objectives.
Subject(s)
Benzylamines/chemistry , Chemistry, Pharmaceutical/methods , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacology , Drug Design , Humans , Inhibitory Concentration 50 , Kinetics , Models, Chemical , Molecular Conformation , Receptors, Serotonin/metabolism , Serotonin/chemistry , Serotonin/metabolism , Structure-Activity RelationshipABSTRACT
Single enantiomer (SS) and (RR) 2-[(phenoxy)(phenyl)methyl]morpholine derivatives 5, 8-23 are inhibitors of monoamine reuptake. Target compounds were prepared using an enantioselective synthesis employing a highly specific enzyme-catalysed resolution of racemic n-butyl 4-benzylmorpholine-2-carboxylate (26) as the key step. Structure-activity relationships established that serotonin and noradrenaline reuptake inhibition are functions of stereochemistry and aryl/aryloxy ring substitution. Consequently, selective SRI, selective NRI and dual SNRIs were all identified. One of these compounds, a potent and selective dual SNRI, (SS)-5a was selected as a candidate for further pre-clinical evaluation.
Subject(s)
Drug Design , Morpholines/chemical synthesis , Morpholines/pharmacology , Norepinephrine/metabolism , Serotonin/metabolism , Cells, Cultured , Humans , Liver/drug effects , Liver/metabolism , Molecular Structure , Morpholines/chemistry , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of sertraline analogues 4-39 which possess polar groups on the fused tetrahydronaphthalene ring, targeting reduced V(d) as a strategy to reduce T(max) and increase rate of elevation of central 5-HT levels, were prepared. These studies led to the successful identification of 22a, which demonstrated equivalent pharmacology and metabolic stability to 1, but which possessed greatly reduced V(d) leading to significantly shorter T(max), in rat pharmacokinetic studies.
