32 research outputs found
Perspectives on phenotypic screening−Screen Design and Assay Technology Special Interest Group
Here we offer perspectives on phenotypic screening based on a wide-ranging discussion entitled “Phenotypic screening, target ID, and multi-omics: enabling more disease relevance in early discovery?” at the Screen Design and Assay Technology Special Interest Group Meeting at the 2023 SLAS Conference. During the session, the authors shared their own experience from within their respective organizations, followed by an open discussion with the audience. It was recognized that while substantial progress has been made towards translating disease-relevant phenotypic early discovery into clinical success, there remain significant operational and scientific challenges to implementing phenotypic screening efforts, and improving translation of screening hits comes with substantial resource demands and organizational commitment. This Perspective assesses progress, highlights pitfalls, and offers possible solutions to help unlock the therapeutic potential of phenotypic drug discovery. Areas explored comprise screening and hit validation strategy, choice of cellular model, moving beyond 2D cell culture into three dimensions, and leveraging high-dimensional data sets downstream of phenotypic screens
Alkylsulfone-containing trisubstituted cyclohexanes as potent and bioavailable chemokine receptor 2 (CCR2) antagonists
We describe novel alkylsulfones as potent CCR2 antagonists with reduced hERG channel activity and improved pharmacokinetics over our previously described antagonists. Several of these new alkylsulfones have a profile that includes functional antagonism of CCR2, in vitro microsomal stability, and oral bioavailability. With this improved profile, we demonstrate that two of these antagonists, 2 and 12, are orally efficacious in an animal model of inflammatory recruitment
Drug-Induced Perturbations of the Bile Acid Pool, Cholestasis, and Hepatotoxicity: Mechanistic Considerations beyond the Direct Inhibition of the Bile Salt Export Pump
Soluble FMS-Like Tyrosine Kinase-1 Is a Circulating Biomarker Associated With Calcific Aortic Stenosis
Solid Phase Synthesis of 1,5-Diarylpyrazole-4-carboxamides: Discovery of Antagonists of the CB-1 Receptor
We have developed a solid phase synthesis route to 1,5-substituted
pyrazole-4-carboxamides with three diversity points aimed at the discovery
of new compounds as potential G-Protein coupled receptor (GPCR) ligands.
The new chemistry involves acylation of a resin bound secondary amine
with a β-ketoester via transamidation, conversion of the resulting
β-ketoamide to the corresponding vinylogous amide, pyrazole
formation upon reaction with a aryl hydrzine, and cleavage of the
product from the resin. Using the reported methodology, we describe
the syntheses of multiple arrays of pyrazoles that were used collectively
to construct a library of more than 1000 analogues. Several members
of this library displayed submicromolar antagonist activities at the
cannabinoid subtype 1 (CB-1) receptor
Solid Phase Synthesis of 1,5-Diarylpyrazole-4-carboxamides: Discovery of Antagonists of the CB-1 Receptor
We have developed a solid phase synthesis route to 1,5-substituted
pyrazole-4-carboxamides with three diversity points aimed at the discovery
of new compounds as potential G-Protein coupled receptor (GPCR) ligands.
The new chemistry involves acylation of a resin bound secondary amine
with a β-ketoester via transamidation, conversion of the resulting
β-ketoamide to the corresponding vinylogous amide, pyrazole
formation upon reaction with a aryl hydrzine, and cleavage of the
product from the resin. Using the reported methodology, we describe
the syntheses of multiple arrays of pyrazoles that were used collectively
to construct a library of more than 1000 analogues. Several members
of this library displayed submicromolar antagonist activities at the
cannabinoid subtype 1 (CB-1) receptor
Solid Phase Synthesis of 1,5-Diarylpyrazole-4-carboxamides: Discovery of Antagonists of the CB-1 Receptor
We have developed a solid phase synthesis route to 1,5-substituted
pyrazole-4-carboxamides with three diversity points aimed at the discovery
of new compounds as potential G-Protein coupled receptor (GPCR) ligands.
The new chemistry involves acylation of a resin bound secondary amine
with a β-ketoester via transamidation, conversion of the resulting
β-ketoamide to the corresponding vinylogous amide, pyrazole
formation upon reaction with a aryl hydrzine, and cleavage of the
product from the resin. Using the reported methodology, we describe
the syntheses of multiple arrays of pyrazoles that were used collectively
to construct a library of more than 1000 analogues. Several members
of this library displayed submicromolar antagonist activities at the
cannabinoid subtype 1 (CB-1) receptor
Solid Phase Synthesis of 1,5-Diarylpyrazole-4-carboxamides: Discovery of Antagonists of the CB-1 Receptor
We have developed a solid phase synthesis route to 1,5-substituted
pyrazole-4-carboxamides with three diversity points aimed at the discovery
of new compounds as potential G-Protein coupled receptor (GPCR) ligands.
The new chemistry involves acylation of a resin bound secondary amine
with a β-ketoester via transamidation, conversion of the resulting
β-ketoamide to the corresponding vinylogous amide, pyrazole
formation upon reaction with a aryl hydrzine, and cleavage of the
product from the resin. Using the reported methodology, we describe
the syntheses of multiple arrays of pyrazoles that were used collectively
to construct a library of more than 1000 analogues. Several members
of this library displayed submicromolar antagonist activities at the
cannabinoid subtype 1 (CB-1) receptor