ABSTRACT
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 to generate a series of benzimidazoles bearing thiazolidin-4-one using scaffold hopping from thiazole 1, our previously described thiazole. Our goal was to discover a potent and permeable small-molecule ADAMTS-5 inhibitor. The results suggest that small compound 22 shows promise as a potent small-molecule ADAMTS-5 inhibitor with good permeability.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , ADAM Proteins/metabolism , ADAMTS5 Protein , Benzimidazoles/pharmacokinetics , Drug Design , Humans , Osteoarthritis/drug therapy , Permeability , Structure-Activity RelationshipABSTRACT
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
A series of thiazole bearing thiazolidin-4-one was discovered via high-throughput screening as non-competitive inhibitors of ADAMTS-5. Compound 31 appeared to give the best ADAMTS-5 inhibition and good selectivity over other metalloproteases.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Thiazoles/pharmacology , ADAM Proteins/metabolism , ADAMTS5 Protein , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
A series of 1,1-dioxothieno[2,3-d]isothiazole (thienosultam) derivatives were designed and synthesized as novel ADAMTS-5 inhibitors for an investigation into a side chain of thienosultam for the S1' pocket. The resulting compounds (19 and 24) show high ADAMTS-5 inhibition and other MMP selectivity, and these compounds show good oral bioavailability.