ABSTRACT
A novel series of EP4 agonists and antagonists have been identified, and then used to validate their potential in the treatment of inflammatory pain. This paper describes these novel ligands and their activity within a number of pre-clinical models of pain, ultimately leading to the identification of the EP4 partial agonist GSK726701A.
Subject(s)
Anti-Inflammatory Agents/chemistry , Isoindoles/chemistry , Receptors, Prostaglandin E, EP4 Subtype/agonists , Animals , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/therapeutic use , Blood Cells/cytology , Blood Cells/drug effects , Blood Cells/metabolism , Dinoprostone/chemistry , Dinoprostone/therapeutic use , Drug Evaluation, Preclinical , Half-Life , Humans , Inhibitory Concentration 50 , Isoindoles/pharmacokinetics , Isoindoles/therapeutic use , Lipopolysaccharides/pharmacology , Pain/drug therapy , Pain/pathology , Pain/veterinary , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Rats , Receptors, Prostaglandin E, EP4 Subtype/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
We describe the medicinal chemistry programme that led to the identification of the EP(1) receptor antagonist GSK269984A (8h). GSK269984A was designed to overcome development issues encountered with previous EP(1) antagonists such as GW848687X and was found to display excellent activity in preclinical models of inflammatory pain. However, upon cross species pharmacokinetic profiling, GSK269984A was predicted to have suboptimal human pharmacokinetic and was thus progressed to a human microdose study.
Subject(s)
Analgesics/chemical synthesis , Chemistry, Pharmaceutical/methods , Inflammation/drug therapy , Nicotinic Acids/chemical synthesis , Pyridines/chemical synthesis , Receptors, Prostaglandin E/antagonists & inhibitors , Analgesics/pharmacology , Animals , Central Nervous System/drug effects , Drug Design , Humans , Hydrogen-Ion Concentration , Inhibitory Concentration 50 , Models, Chemical , Nicotinic Acids/pharmacology , Pyridines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Herein we describe the medicinal chemistry programme to identify a potential back-up compound to the EP(1) receptor antagonist GW848687X. This work started with the lipophilic 1,2-biaryl benzene derivative 4 which displayed molecular weight of 414.9g/mol and poor in vivo metabolic stability in the rat and resulted in the identification of compound 7i (GSK345931A) which demonstrated good metabolic stability in the rat and lower molecular weight (381.9g/mol). In addition, 7i (GSK345931A) showed measurable CNS penetration in the mouse and rat and potent analgesic efficacy in acute and sub-chronic models of inflammatory pain.
Subject(s)
Inflammation/drug therapy , Pain/drug therapy , Pyridines/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Animals , Drug Evaluation, Preclinical , Pyridines/chemistry , Pyridines/therapeutic use , Rats , Receptors, Prostaglandin E, EP1 Subtype , Structure-Activity RelationshipABSTRACT
Replacement of the carboxylic acid group in a series of previously described methylene-linked pyrazole EP(1) receptor antagonists led to the discovery of amide, reversed amide and carbamate derivatives. Two compounds, 10a and 10b, were identified as brain penetrant compounds and both demonstrated efficacy in the CFA model of inflammatory pain.
Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Analgesics/chemistry , Animals , Brain/drug effects , Central Nervous System/drug effects , Combinatorial Chemistry Techniques , Disease Models, Animal , Dose-Response Relationship, Drug , Molecular Structure , Pain Measurement , Pyrazoles/chemistry , Rats , Receptors, Prostaglandin E, EP1 Subtype , Structure-Activity RelationshipABSTRACT
This paper details the SAR of 1,5-biaryl pyrrole derivatives with substituents in the 2-, 4-, and 5-positions of the benzoic acid group as EP1 receptor antagonists. Substitution at the 2-position was poorly tolerated, whereas only fluorine was tolerated at the 4-position. In contrast, a range of substituents at the 5-position were discovered which enhanced the in vitro affinity and led to compounds with promising oral exposure. Three derivatives showed efficacy in a preclinical model of inflammatory pain when dosed orally to rats.
Subject(s)
Benzoates/chemical synthesis , Benzoates/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Animals , Benzoates/chemistry , CHO Cells , Cricetinae , Cricetulus , Inflammation/chemically induced , Inflammation/complications , Pain/drug therapy , Pain/etiology , Rats , Receptors, Prostaglandin E, EP1 Subtype , Structure-Activity RelationshipABSTRACT
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
Herein we describe the SAR of 1,5-biaryl pyrrole derivatives, with substituents in the 6-position of the benzoic acid moiety, as EP(1) receptor antagonists. Substitution at this position was well tolerated and led to the identification of several analogues with high affinity for the EP(1) receptor that displayed good efficacy in the established FCA model of inflammatory pain. Furthermore, several analogues were prepared which combined substitution at the 5- and 6-positions as well as derivatives with an aromatic ring fused to the 5- and 6-positions.
Subject(s)
Benzoates/chemical synthesis , Benzoates/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Area Under Curve , Brain/metabolism , CHO Cells , Cell Membrane/drug effects , Cell Membrane/metabolism , Cricetinae , Cricetulus , Cytochrome P-450 Enzyme System/metabolism , Dose-Response Relationship, Drug , Half-Life , Humans , Indicators and Reagents , Pain/drug therapy , Pain Measurement/drug effects , Rats , Receptors, Prostaglandin E, EP1 Subtype , Structure-Activity RelationshipABSTRACT
The preliminary SAR of a series of novel 1,5-biaryl pyrrole EP1 receptor antagonists derived from compound 1 is described. Replacement of the benzyl group of 1 with isosteric groups was investigated. The most effective replacement was found to be the isobutyl group. The cyclopentylmethyl and cyclohexylmethyl groups were also effective benzyl replacements. The cyclohexylmethyl derivative 19 demonstrated the lowest metabolic clearance within this series. In addition, several high affinity substituted benzyl analogues were also identified. Compound 39 was found to have good bioavailability in rats and demonstrated efficacy in the established FCA preclinical model of inflammatory pain with a calculated ED50 of 9.2mg/kg.
