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Because of the limitations and liabilities of current testosterone therapies, non-steroidal tissue-selective androgen receptor modulators may provide a clinically meaningful advance in therapy. Using a functional cell-based assay AC-262536 was identified as a potent and selective AR ligand, with partial agonist activity relative to the natural androgen testosterone. A 2-week chronic study in castr
Rapid addition of Grignard reagents to pyridine N-oxides under mild conditions gave stereodefined dienal oximes in good to excellent yields. This reaction provides an efficient access to substituted olefins with defined stereochemistry that are potentially of interest as bioactives themselves or as versatile synthetic intermediates.
Using a high-throughput functional screen, the atypical L-type Ca 2+ channel blocker diltiazem was discovered to be an agonist at the human ghrelin (GHSR1a) receptor. In cellular proliferation, Ca2+ mobilization, and bioluminescence resonance energy transfer (BRET-2) assays, diltiazem was a partial agonist at GHSR1a receptors, with 50 to 80% relative efficacy compared with the GHSR1a peptide agoni
A 30-membered library of amides based on the potent urotensin II (UII) receptor agonist FL104, has been synthesized from ten different carboxylic acids and three amines. A synthetic protocol producing the amides in 47-98% yield has been developed in which the purification involved only extractions and in a few cases filtration through an ion-exchange resin. It was found that 5 mg of starting mater
We have developed a new assay for measuring epidermal growth factor receptor (EGFR) activation using the bioluminescence resonance energy transfer (BRET) technology, which directly measures the recruitment of signaling proteins to activated EGFR. Our results demonstrate that EGFR BRET assays precisely measure the pharmacology and signaling properties of EGFR expressed in human embryonic kidney 293
Six different series of nonpeptidic urotensin II receptor agonists have been synthesized and evaluated for their agonistic activity in a cell-based assay (R-SAT). The compounds are ring-opened analogues of the isochromanone-based agonist AC-7954 with different functionalities constituting the linker between the two aromatic ring moieties. Several of the compounds are highly potent and efficacious,
Drugs targeting retinoid receptors have been developed to treat a variety of therapeutic indications, but their success has been limited in part due to lack of selectivity. A novel functional cell-based assay R-SAT™ was employed to screen a small molecule chemical library and identify a variety of novel RAR agonists with various subtype selectivities, including RARβ/γ and RARγ selective agonists.
Drugs that antagonize D2-like receptors are effective antipsychotics, but the debilitating movement disorder side effects associated with these drugs cannot be dissociated from dopamine receptor blockade. The "atypical" antipsychotics have a lower propensity to cause extrapyramidal symptoms (EPS), but the molecular basis for this is not fully understood nor is the impact of inverse agonism upon th
An efficient strategy for solution-phase parallel synthesis of substituted 1,2-diarylethanes is described. A stilbene library was initially generated by Wittig olefination utilizing amino-labeled phosphines. The stilbene analogues were obtained in high yields and excellent purities after solid-phase extraction. Subsequent reduction of the stilbene libraries simultaneously unmasked functional group
A series of analogues of the selective non-peptide urotensin II (UII) receptor agonist 3-(4-chlorophenyl)-3-(2-dimethylaminoethyl)-isochroman-1-one (AC-7954, 1) was synthesized and evaluated for UII agonist activity using a functional cell-based assay. The introduction of a methyl group in the 4-position resulted in a complete loss of activity, whereas substituents in the aromatic rings were benef
Rationale: Clozapine is a unique antipsychotic, with efficacy against positive symptoms in treatment-resistant schizophrenic patients, and the ability to improve cognition and treat the negative symptoms characteristic of this disease. Despite its unique clinical actions, no specific molecular mechanism responsible for these actions has yet been described. Objectives and methods: To comprehensivel
A flexible, multistep parallel synthesis of spiperone analogues is described. A library of 4-substituted piperidines, assembled utilizing reductive amination and acylation protocols, was alkylated either homogeneously or heterogeneously, exploiting a product release only concept, to afford an oxa-series of spiperone analogues. Screening of the products at 5-HT2 and D2 receptors revealed 5-HT(2A) a
A novel solid phase synthesis of tertiary amines involving iodide-induced cleavage of the N-O bond of resin bound alkoxyammonium intermediates is described. The quaternary intermediates were assembled via sequential reductive aminations followed by alkylation. Cleavage from the solid support was induced by iodide ion or base, to afford the target tertiary amines in excellent purity.
A functional cell-based screen identified 3-(4-chlorophenyl)-3-(2-(dimethylamino)ethyl)isochroman-1-one hydrochloride (AC-7954, 1) as a nonpeptidic agonist of the urotensin-II receptor. Racemic 1 had an EC50 of 300 nM at the human UII receptor and was highly selective. Testing of the enantiopure (+)- and (-)-1 revealed that the UII receptor activity of racemic 1 resides primarily in (+)-1. Being a
Rapid parallel synthesis of thioamides is described. A library of amides, synthesised by mixing acyl chlorides and diamines, was transformed into the corresponding thioamides utilising Lawesson's reagent as the oxygen/sulphur exchange reagent. Purification by solid-phase extraction afforded the library members in adequate purities and yields. (C) 2000 Elsevier Science Ltd.
Semiempirical and ab initio quantum chemical computations indicate that the intermediate formed prior to the selectivity-determining methyl transfer step in the reaction between glycosides and trimethylaluminum is a strongly hydrogen-bended equilibrium OH...C = O-H...C, which is proposed to be an important selectivity promoting factor in the alkyl transfer reaction.
The primary aim of this thesis is to develop a theoretical model that enhances our understanding of entrepreneurial learning as a process by which personalized streams of experience become routinized and embedded in venture-wide behaviors. The aim is realized by exploring entrepreneurial learning as an experiential multilevel process. This process begins with learning at the individual level, whic
Simple lactol ethers undergo ring cleavage to give acyclic chain-extended products on treatment with organoaluminium and organotitanium reagents.
Combinations of Lewis acids and nucleophilic reagents trigger endo-opening of the furanoside ring of methyl furanosides 1, 10 and 13, resulting in the attachment of the nucleophilic group at C-1 of the carbohydrate. The stereoselectivity in the C-C bond-forming step is low for the 2-deoxyfuranosides but very high (dr 1:99) for the furanosides carrying a methoxy group in the 2-position when a combi
A number of pentopyranoside derivatives were treated with Me 3 Al in order to investigate the influence of structural parameters on the methyl group transfer in the endocyclic alkylative cleavage reaction of these substrates. A cyclic CH ··· O hydrogen bonded model is suggested as an intermediate, which is used to explain the stereoselectivities for different substrates. In several, cases the dia
