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.
Subject(s)
Drug Design , Hepacivirus/enzymology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Crystallography, X-Ray , Dogs , Drug Stability , Hepacivirus/drug effects , Humans , Injections, Intravenous , Lactams/chemical synthesis , Lactams/pharmacokinetics , Lactams/pharmacology , Models, Biological , Molecular Structure , Protease Inhibitors/pharmacokinetics , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Rats , Viral Nonstructural Proteins/metabolismABSTRACT
[reaction: see text] In this, the first of two letters, we outline the use of the pyrrolidine-5,5-trans-lactam template to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. The hitherto unreported reaction of the acyl iminium ion precursor 4 with dialkyl-substituted silyl ketene acetals (e.g., 8b) is described. Compound 12b, with a spirocyclobutyl P1 substituent and a cyclopropylacyl substituent on the lactam nitrogen, has a k(obs)/I of 400 M(-)(1) s(-)(1) and demonstrates activity in a replicon cell-based surrogate HCV assay.
Subject(s)
Hepacivirus/enzymology , Lactams/chemical synthesis , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Pyrrolidines/chemical synthesis , Serine Endopeptidases/metabolism , Viral Nonstructural Proteins/antagonists & inhibitors , Cell Line , Drug Design , Drug Stability , Hepacivirus/drug effects , Humans , Lactams/chemistry , Molecular Structure , Protease Inhibitors/chemistry , Pyrrolidines/chemistry , Viral Nonstructural Proteins/metabolismABSTRACT
[reaction: see text] In this, the second of two letters, we describe the elaboration of the pyrrolidine-5,5-trans-lactam template to delineate the requirements for optimal substitution of the pyrrolidine and lactam nitrogen atoms. Central to the strategy is the use of rapid iterative synthesis in conjunction with X-ray crystal structure determination of ligand-protein complexes.
Subject(s)
Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Lactams/chemical synthesis , Pyrrolidines/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Cell Line , Crystallography, X-Ray , Enzyme Inhibitors/pharmacology , Hepacivirus/drug effects , Hepacivirus/enzymology , Inhibitory Concentration 50 , Lactams/chemistry , Lactams/pharmacology , Models, Molecular , Molecular Structure , Protein Conformation , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Viral Nonstructural Proteins/metabolismABSTRACT
Using a pyrrolidine-5,5-trans-lactam template, we have designed small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. Compound 11a, with an alpha-ethyl P1 substituent and a Boc-valine substituent at the pyrrolidine nitrogen, has an IC(50)=30 microM.
