Subject(s)
Nicotinic Agonists/pharmacology , Receptors, Nicotinic/chemistry , Allosteric Regulation/drug effects , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Drug Discovery/methods , Humans , Inflammation/drug therapy , Mental Disorders/drug therapy , Nicotinic Agonists/therapeutic use , Receptors, Nicotinic/physiology , Structure-Activity Relationship , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
A strategy has been developed for a rapid seven-step construction of a chiral, nonracemic vinyl cyclopentanone building block as part of a synthetic approach to viridenomycin, using a diastereo- and enantioselective Mukaiyama aldol and intramolecular Knoevenagel condensation as key steps.
Subject(s)
Aldehydes/chemistry , Cyclopentanes/chemistry , Lactams/chemical synthesis , StereoisomerismABSTRACT
A rational structure-activity relationship study around compound (1) is reported. The lead optimisation programme led to the identification of sulfonamide (25), a molecule combining dopamine D2/D3 receptor antagonism with serotonin 5-HT2A, 5-HT2C, 5-HT6 receptor antagonism for an effective treatment of schizophrenia. Compound (25) was shown to possess the required in vivo activity with no EPS liability.
Subject(s)
Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/pharmacology , Alkylation , Cytochrome P-450 Enzyme System/chemistry , Cytochrome P-450 Enzyme System/metabolism , Dopamine Antagonists/chemical synthesis , Dopamine Antagonists/pharmacology , Dopamine D2 Receptor Antagonists , Drug Design , Humans , Receptor, Serotonin, 5-HT2A/drug effects , Receptor, Serotonin, 5-HT2C/drug effects , Receptors, Dopamine D3/antagonists & inhibitors , Receptors, Serotonin/drug effects , Recombinant Proteins/drug effects , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacologyABSTRACT
A number of 1,6-diphenyl-1,3,5-hexatrienes of varying alkene geometries were stereoselectively prepared from just two starting materials: iodobenzene and 4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane via a series of Heck, Suzuki-Miyaura and stereocontrolled iododeboronation reactions. These results demonstrate how 4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane can be used as a genuine two-carbon vinyl-dianion building block in stereocontrolled polyene synthesis.
Subject(s)
Alkenes/chemical synthesis , Boron Compounds/chemistry , Dioxanes/chemistry , Iodobenzenes/chemistry , Ligands , Molecular Structure , StereoisomerismABSTRACT
Novel 5-HT(7) receptor antagonists containing the benzocycloheptanone core were identified from high throughput screening. Molecular modelling and SAR studies have converted these intractable hits into a more potent, selective and tractable series, exemplified by compound (25), SB-691673.
Subject(s)
Receptors, Serotonin/drug effects , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Cytochrome P-450 Enzyme System/drug effects , Drug Design , Drug Evaluation, Preclinical , Humans , Indicators and Reagents , Isoenzymes/drug effects , Models, Molecular , Structure-Activity RelationshipABSTRACT
A focused SAR study around the previously reported selective 5-HT(7) receptor antagonist, SB-269970-A has resulted in the identification of a structurally related analogue having an improved pharmacokinetic profile. Replacement of the phenolic group in SB-269970-A with an indole moiety, and replacement of the piperidinyl 4-methyl group with a heterocyclic ring system proved to be the key changes leading to the identification of SB-656104-A.
Subject(s)
Phenols/pharmacokinetics , Pyrrolidines/pharmacokinetics , Receptors, Serotonin/chemistry , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacokinetics , Animals , Blood-Brain Barrier , Heterocyclic Compounds , Indoles , Phenols/chemical synthesis , Phenols/pharmacology , Protein Binding , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Rats , Serotonin Antagonists/pharmacology , Structure-Activity Relationship , Sulfonamides/pharmacokineticsABSTRACT
Arylnitroso dienophiles exist in equilibrium with their dimeric counterparts, which in turn form stable bidentate complexes with scandium(III) triflate and react with cyclohexadiene to give the corresponding Diels-Alder adduct at the same rate as the normal thermal process.
