ABSTRACT
We describe a medicinal chemistry approach to the discovery of a novel EP1 antagonist exhibiting high potency and good pharmacokinetics. Our starting point is 1, an EP1 receptor antagonist that exhibits pharmacological efficacy in cystometry models following intravenous administration. Despite its good potency in vitro, the high lipophilicity of 1 is a concern in long-term in vivo studies. Further medicinal chemistry efforts identified 4 as an improved lead compound with good in vitro ADME profile applicable to long term in vivo studies. A rat fracture study was conducted with 4 for 4â¯weeks to validate its utility in bone fracture healing. The results suggest that this EP1 receptor antagonist stimulates callus formation and thus 4 has potential for enhancing fracture healing.
Subject(s)
Drug Discovery , Fracture Healing/drug effects , Fractures, Bone/drug therapy , Receptors, Prostaglandin E, EP1 Subtype/antagonists & inhibitors , Thiazoles/pharmacology , Animals , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Fractures, Bone/metabolism , Madin Darby Canine Kidney Cells/drug effects , Madin Darby Canine Kidney Cells/metabolism , Madin Darby Canine Kidney Cells/pathology , Mice , Mice, Knockout , Molecular Structure , Receptors, Prostaglandin E, EP1 Subtype/deficiency , Receptors, Prostaglandin E, EP1 Subtype/metabolism , Structure-Activity Relationship , Thiazoles/chemistryABSTRACT
We have designed a series of potent EP1 receptor antagonists. These antagonists are a series of 2-(1H-indazol-1-yl)-thiazoles in which the core structure was replaced with pyrazole-phenyl groups. In preliminary conscious rat cystometry experiments, two representative candidates, 2 and 22, increased bladder capacity. In particular, the increase using 22 was approximately 2-fold that of the baseline. More detailed profiling of this compound and further optimization of this series promises to provide a novel class of drug for treating overactive bladder (OAB).
Subject(s)
Indazoles/chemistry , Receptors, Prostaglandin E, EP1 Subtype/antagonists & inhibitors , Thiazoles/chemistry , Animals , Drug Evaluation, Preclinical , Half-Life , Humans , Protein Binding , Rats , Receptors, Prostaglandin E, EP1 Subtype/metabolism , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Thiazoles/therapeutic use , Urinary Bladder/drug effects , Urinary Bladder, Overactive/drug therapyABSTRACT
We describe a medicinal chemistry approach for generating a series of 2-(1H-pyrazol-1-yl)thiazoles as EP1 receptor antagonists. To improve the physicochemical properties of compound 1, we investigated its structure-activity relationships (SAR). Optimization of this lead compound provided small compound 25 which exhibited the best EP1 receptor antagonist activity and a good SAR profile.
Subject(s)
Pyrazoles/chemistry , Pyrazoles/pharmacology , Receptors, Prostaglandin E, EP1 Subtype/antagonists & inhibitors , Thiazoles/chemistry , Thiazoles/pharmacology , Humans , Protein Binding/drug effects , Pyrazoles/chemical synthesis , Pyrazoles/metabolism , Receptors, Prostaglandin E, EP1 Subtype/metabolism , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/metabolismABSTRACT
We describe a medicinal chemistry approach to generate a series of 2-(1H-pyrazol-1-yl)thiazole compounds that act as selective EP1 receptor antagonists. The obtained results suggest that compound 12 provides the best EP1 receptor antagonist activity and demonstrates good oral pharmacokinetics.
Subject(s)
Pyrazoles/pharmacology , Receptors, Prostaglandin E, EP1 Subtype/antagonists & inhibitors , Thiazoles/pharmacology , Animals , Humans , Mice , Models, Molecular , Pyrazoles/pharmacokinetics , Receptors, Prostaglandin E, EP1 Subtype/metabolism , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacokineticsABSTRACT
In this study the first PDE4B selective inhibitor is described. Optimization of lead 2-arylpyrimidine derivatives afforded a series of potent PDE4B inhibitors with >100-fold selectivity over the PDE4D isozyme. With a good pharmacokinetic profile, a selected compound exhibited potent anti-inflammatory effects in vivo and showed less emesis compared with Cilomilast.