ABSTRACT
The discovery of a series of selective EP1 receptor antagonists based on a 1,2-diarylcyclopentene template is described. After defining the structural requirements for EP1 potency and selectivity, heterocyclic rings were incorporated to reduce logD and improve in vitro pharmacokinetic properties. The 2,6-substituted pyridines and pyridazines gave an appropriate balance of potency, in vivo pharmacokinetic properties and a low potential for inhibiting a range of CYP450 enzymes. From this series, GW848687X was shown to have an excellent profile in models of inflammatory pain and was selected as a development candidate.
Subject(s)
Alprostadil/metabolism , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclopentanes/chemical synthesis , Cyclopentanes/pharmacology , Inflammation/drug therapy , Pain/drug therapy , Pyridines/chemical synthesis , Pyridines/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Biological Availability , Cytochrome P-450 Enzyme System/metabolism , Dogs , Dose-Response Relationship, Drug , Freund's Adjuvant , Half-Life , Inflammation/chemically induced , Inflammation/complications , Pain/etiology , RatsABSTRACT
We describe the generation of novel EP(1) receptor antagonists by investigation of thiophene isosteres. In addition, we disclose preliminary in vitro and in vivo DMPK for selected compounds.
Subject(s)
Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Animals , In Vitro Techniques , Rats , Receptors, Prostaglandin E, EP1 SubtypeABSTRACT
The pyrrolidine-5,5-trans-lactam template was used to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease displaying potent activity in the replicon cell-based assay. The activity of this series is not dependent upon its chemical reactivity and molecules have been synthesised which combine enhanced biochemical potency with improved plasma stability. Promising initial pharmacokinetic data indicating the potential for further optimisation of this series into low molecular weight, drug-like inhibitors is presented.
