ABSTRACT
As part of an on-going lead optimisation effort, a cross screening exercise identified an aryl sulphonyl amide hit that was optimised to afford a highly potent series of ghrelin receptor agonists.
Subject(s)
Chemistry, Pharmaceutical/methods , Ghrelin/chemistry , Receptors, Ghrelin/antagonists & inhibitors , Sulfones/chemistry , Administration, Oral , Animals , Biological Availability , Drug Design , Growth Hormone/chemistry , Male , Models, Chemical , Protein Processing, Post-Translational , Rats , Rats, Sprague-Dawley , Receptors, Ghrelin/chemistry , Structure-Activity RelationshipABSTRACT
A series of small molecule orally bioavailable ghrelin receptor agonists have been identified through systematic optimisation of a high throughput screening hit.
Subject(s)
Indoles/pharmacology , Receptors, Ghrelin/agonists , Sulfonamides/pharmacology , Administration, Oral , Animals , Biological Availability , Fluorescence , Indoles/chemical synthesis , Male , Molecular Structure , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT1B/metabolism , Receptors, Ghrelin/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesisABSTRACT
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Factor Xa Inhibitors , Pyrrolidinones/chemistry , Serine Proteinase Inhibitors/chemistry , Animals , Anticoagulants/chemistry , Anticoagulants/pharmacokinetics , Anticoagulants/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Hydrophobic and Hydrophilic Interactions , Male , Models, Molecular , Pyrrolidinones/pharmacokinetics , Pyrrolidinones/pharmacology , Rats , Rats, Sprague-Dawley , Serine Proteinase Inhibitors/pharmacokinetics , Serine Proteinase Inhibitors/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A silyl-modified variant of the Bellus-Claisen rearrangement is described; the generality of this rearrangement has been demonstrated with a range of allylic amines and ketenes.
Subject(s)
Alkenes/chemistry , Allyl Compounds/chemistry , Amines/chemistry , Ethylenes/chemistry , Ketones/chemistry , Mesylates/chemistry , Models, Chemical , Cyclization , Esters , Molecular Structure , Stereoisomerism , Trimethylsilyl CompoundsABSTRACT
Structure-based drug design was exploited in the synthesis of 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group with acyclic tertiary amide termini. Optimized hydrophobic contacts of one amide substituent in P4 were complemented by hydrophobicity-modulating features in the second, producing potent fXa inhibitors including examples with excellent anticoagulant properties.
Subject(s)
Alanine/chemistry , Amides/chemistry , Antithrombin III/chemical synthesis , Antithrombin III/pharmacology , Drug Design , Pyrroles/chemistry , Anticoagulants/chemical synthesis , Anticoagulants/chemistry , Anticoagulants/metabolism , Anticoagulants/pharmacology , Antithrombin III/chemistry , Antithrombin III/metabolism , Binding Sites , Crystallography, X-Ray , Factor Xa/chemistry , Factor Xa/metabolism , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of novel, non-basic 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group, was designed and synthesised. Within this series, the N-2-(morpholin-4-yl)-2-oxoethyl derivative 24 was shown to be a potent, selective fXa inhibitor with good anticoagulant activity. Moreover, 24 possessed highly encouraging rat and dog pharmacokinetic profiles with excellent oral bioavailabilities in both species.
