ABSTRACT
A series of α7 nicotinic acetylcholine receptor full-agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Systematic exploration of the structure-activity relationships for both α7 potency and selectivity with respect to interaction with the hERG channel are described. Further profiling led to the identification of compound 22, a potent full agonist showing efficacy in the novel object recognition model of cognition enhancement.
Subject(s)
Cognition/drug effects , Nicotinic Agonists/pharmacology , Receptors, Nicotinic/drug effects , Animals , Dogs , Nicotinic Agonists/chemistry , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
A series of α7 nicotinic acetylcholine receptor full agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Early lead 1 was found to have a limited therapeutic index with respect to its potential for cardiovascular side effects. Further optimisation of this series led to the identification of 22 a potent full agonist showing efficacy at a dose of 0.1mg/kg in the novel object recognition model of cognition enhancement. Comparison of 1 with 22 demonstrated the latter to have an improved oral pharmacokinetic profile and cardiovascular therapeutic index.
Subject(s)
Cognition/drug effects , Nicotinic Agonists/pharmacology , Receptors, Nicotinic/drug effects , Animals , Dose-Response Relationship, Drug , Rabbits , Receptors, Nicotinic/chemistry , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
We describe the discovery and optimization of a novel series of benzofuran EP(1) antagonists, leading to the identification of 26d, a novel nonacidic EP(1) antagonist which demonstrated efficacy in preclinical models of chronic inflammatory pain.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Benzofurans/chemistry , Receptors, Prostaglandin E, EP1 Subtype/antagonists & inhibitors , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Benzofurans/pharmacokinetics , Benzofurans/therapeutic use , Cell Line , Disease Models, Animal , Dogs , Drug Evaluation, Preclinical , Pain/drug therapy , Rats , Receptors, Prostaglandin E, EP1 Subtype/metabolism , Structure-Activity RelationshipABSTRACT
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
We describe the medicinal chemistry approach that generated a novel indole series of EP(1) receptor antagonists. The SAR of this new template was evaluated and culminated in the identification of compound 12g which demonstrated in vivo efficacy in a preclinical model of inflammatory pain.
Subject(s)
Indoles/chemical synthesis , Indoles/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Receptors, Prostaglandin E/metabolism , Animals , Humans , Hydrogen Bonding , Indoles/chemistry , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Rats , Receptors, Prostaglandin E, EP1 Subtype , Structure-Activity Relationship , Thiazoles/chemistryABSTRACT
We describe the SAR, in terms of heterocyclic replacements, for a series of pyrazole EP(1) receptor antagonists. This study led to the identification of several aromatic heterocyclic replacements for the pyrazole in the original compound. Investigation of replacements for the methylene linker uncovered disparate SAR in the thiazole and pyridine series.
Subject(s)
Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Models, Molecular , Molecular Structure , Protein Binding , 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
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.
