ABSTRACT
An ultra high-pressure liquid chromatography/mass spectrometry (UHPLC/MS) separation and analysis method has been devised for open access analysis of synthetic reactions used in the production of DNA-encoded chemical libraries. The aqueous mobile phase is 100mM hexafluoroisopropanol and 8.6mM triethylamine; the organic mobile phase is methanol. The UHPLC separation uses a C18 OST column (50mm×2.1mm×1.7µm) at 60°C, with a flow rate of 0.6mL/min. Gradient concentration is from 10 to 40% B in 1.0min, increasing to 95% B at 1.2min. Cycle time was about 5min. This method provides a detection limit of a 20-mer oligonucleotide by mass spectrometry of better than 1pmol on-column. Linear UV response for 20-mer extends from 2 to 200pmol/µL in concentration, same-day relative average deviations are less than 5% and bias (observed minus expected) is less than 10%. Deconvoluted mass spectra are generated for components in the predicted mass range using a maximum entropy algorithm. Mass accuracy of deconvoluted spectra is typically 20ppm or better for isotopomers of oligonucleotides up to 7000Da.
Subject(s)
Chromatography, High Pressure Liquid/methods , DNA/chemistry , Gene Library , Mass Spectrometry/methods , Oligonucleotides/chemistry , Algorithms , DNA/chemical synthesis , Oligonucleotides/analysis , Spectrometry, Mass, Electrospray Ionization , ThermodynamicsABSTRACT
To address the hERG liability of MCHR1 antagonists such as 1 and 2, new analogs such as 4 and 5 that incorporated a polar heteroaryl group were designed and synthesized. Biological evaluation confirmed that these new analogs retained MCH R1 activity with greatly attenuated hERG liabilities as indicated in the Rb efflux assay.
Subject(s)
Chemistry, Pharmaceutical/methods , Heptanes/chemistry , Hexanes/chemistry , Receptors, Somatostatin/antagonists & inhibitors , Animals , Drug Design , Drug Evaluation, Preclinical , Fishes , Humans , Kinetics , Mice , Models, Chemical , Molecular Structure , Obesity/drug therapyABSTRACT
Gamma-secretase is a key enzyme involved in the production of beta-amyloid peptides which are believed to play a critical role in the onset and progression of Alzheimer's disease (AD). As such, inhibition of gamma-secretase has been an attractive approach to AD therapy. In this paper, the design, synthesis, and evaluation of tetrahydroquinoline and pyrrolidine sulfonamide carbamates as gamma-secretase inhibitors are described.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Carbamates/chemistry , Carbamates/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Alzheimer Disease/enzymology , Carbamates/chemical synthesis , Drug Design , Enzyme Inhibitors/chemical synthesis , Humans , Pyrrolidines/chemistry , Quinolines/chemistry , Structure-Activity Relationship , Sulfonamides/chemical synthesisABSTRACT
Melanin concentrating hormone (MCH) plays an important role in the regulation of food intake and energy balance in mammals. MCH-1 receptor (MCH1R) deficient mice are lean and resistant to diet-induced obesity. As such, MCH1R antagonists are believed to have potential as possible treatments for obesity. The discovery of a novel class of tetralin ureas as potent MCH1R antagonists is described herein.
Subject(s)
Receptors, Somatostatin/antagonists & inhibitors , Tetrahydronaphthalenes/chemical synthesis , Tetrahydronaphthalenes/pharmacology , Urea/analogs & derivatives , Urea/pharmacology , Animals , Binding, Competitive/drug effects , CHO Cells , Cricetinae , Cricetulus , Drug Design , Humans , Mice , Mice, Knockout , Rats , Receptors, Somatostatin/genetics , Structure-Activity Relationship , Tetrahydronaphthalenes/pharmacokinetics , Tissue Distribution , Urea/pharmacokineticsABSTRACT
-4-Amino-2-arylbutylbenzamides such as 1 were identified as micromolar MCH 1 receptor (MCH1R) antagonists via screening using a scintillation proximity assay based on [125I]-MCH binding to recombinant, human MCH1R. Subsequent lead optimization efforts using solid-phase parallel synthesis resulted in the defined structure-activity relationships and the identification of 4-amino-2-biarylbutylureas, such as 11g, as potent single digit nanomolar MCH1R antagonists.
Subject(s)
Receptors, Somatostatin/antagonists & inhibitors , Urea/chemical synthesis , Urea/pharmacology , Combinatorial Chemistry Techniques , Drug Evaluation, Preclinical , Humans , Molecular Structure , Structure-Activity Relationship , Urea/analogs & derivativesABSTRACT
An encoded combinatorial library based on aryl and biaryl piperidine scaffolds was designed and synthesized. Screening of this library resulted in the discovery of high-nanomolar biaryl piperidine-based MCH1 receptor antagonists. Follow-up optimization using a parallel synthesis provided potent, single digit nanomolar antagonists.
