ABSTRACT
Despite the extensive literature describing the role of the ATP-gated P2X(3) receptors in a variety of physiological processes the potential of antagonists as therapeutic agents has been limited by the lack of drug-like selective molecules. In this paper we report the discovery and optimization of RO-85, a novel drug-like, potent and selective P2X(3) antagonist. High-throughput screening of the Roche compound collection identified a small hit series of heterocyclic amides from a large parallel synthesis library. Rapid optimization, facilitated by high-throughput synthesis, focusing on increasing potency and improving drug-likeness resulted in the discovery of RO-85.
Subject(s)
Drug Discovery/methods , Purinergic P2 Receptor Antagonists , Pyrazoles/chemistry , Pyrazoles/metabolism , Pyrazoles/pharmacology , Thiophenes/chemistry , Thiophenes/metabolism , Thiophenes/pharmacology , Animals , Humans , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Protein Binding/physiology , Rats , Receptors, Purinergic P2/metabolism , Receptors, Purinergic P2X3 , Structure-Activity RelationshipABSTRACT
A series of androgen receptor modulators based on 8H-[1,4]oxazino[2,3-f]quinolin-8-ones was synthesized and evaluated in an androgen receptor transcriptional activation assay. The most potent analogues from the series exhibited single-digit nanomolar potency in vitro. Compound 18h demonstrated full efficacy in the maintenance of muscle weight, at 10 mg/kg, with reduced activity in prostate weight in an in vivo model of androgen action.
Subject(s)
Oxazines/chemical synthesis , Oxazines/pharmacology , Quinolones/chemical synthesis , Quinolones/pharmacology , Receptors, Androgen/drug effects , Animals , Cell Line , Dose-Response Relationship, Drug , Humans , Indicators and Reagents , Male , Models, Molecular , Orchiectomy , Rats , Receptors, Androgen/chemistry , Receptors, Progesterone/chemistry , Receptors, Progesterone/drug effects , Receptors, Somatotropin/chemistry , Receptors, Somatotropin/drug effects , Structure-Activity Relationship , Testosterone/bloodABSTRACT
New RXR-selective modulators possessing a 6-fluoro trienoic acid moiety (6Z olefin) or a fluorinated/heterocyclic-substituted benzene core ring, were synthesized in an expedient and selective way. A subset of these compounds was evaluated for their metabolic properties (exposure in IRC male mice) and show a dramatic increase of exposure compared to our reference compound, 3 (LG101506).
Subject(s)
Coumarins/chemical synthesis , Coumarins/pharmacology , Receptors, Retinoic Acid/physiology , Transcription Factors/physiology , Animals , Binding, Competitive , Cell Line , Drug Design , Kinetics , Male , Mice , Receptors, Retinoic Acid/drug effects , Retinoic Acid Receptor alpha , Retinoid X Receptors , Transcription Factors/drug effects , Tretinoin/pharmacokinetics , Retinoic Acid Receptor gammaABSTRACT
Retinoid X receptor:peroxisome proliferative-activated receptor (RXR:PPAR) heterodimers play a critical role in the regulation of glucose (RXR/PPARgamma) and lipid metabolism (RXR/PPARalpha). Previously, we described a concise structure-activity relationship study of selective RXR modulators possessing a (2E,4E,6Z)-3-methyl-7-(3,5-dialkyl-6-alkoxyphenyl)-octa-2,4,6-trienoic acid scaffold. These studies were focused on the 2-position alkoxy side chain. We describe here the design and synthesis of a novel series of RXR selective modulators possessing the same aromatic core structure with the addition of a ring locked 6-7-Z-olefin on the trienoic acid moiety. The synthesis and structure-activity relationship studies of these 6,7-locked cyclopentenyl, phenyl, thienyl, furan, and pyridine-trienoic acid derivatives is presented herein.