Publications by authors named "Igor Goljer"

1. GSK2140944 is a novel bacterial topoisomerase inhibitor in development for the treatment of bacterial infections. The metabolism and disposition in healthy human subjects was investigated.

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The pharmacokinetics, metabolism, and excretion of dolutegravir, an unboosted, once-daily human immunodeficiency virus type 1 integrase inhibitor, were studied in healthy male subjects following single oral administration of [(14)C]dolutegravir at a dose of 20 mg (80 μCi). Dolutegravir was well tolerated, and absorption of dolutegravir from the suspension formulation was rapid (median time to peak concentration, 0.5 h), declining in a biphasic fashion.

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A series of phenyl sulfone substituted quinoxaline were prepared and the lead compound 13 (WYE-672) was shown to be a tissue selective LXR Agonist. Compound 13 demonstrated partial agonism for LXRbeta in kidney HEK-293 cells but did not activate Gal4 LXRbeta fusion proteins in huh-7 liver cells. Although 13 showed potent binding affinity to LXRbeta (IC(50) = 53 nM), it had little binding affinity for LXRalpha (IC(50) > 1.

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Methylnaltrexone (MNTX), a selective mu-opioid receptor antagonist, functions as a peripherally acting receptor antagonist in tissues of the gastrointestinal tract. This report describes the metabolic fate of [(3)H]MNTX or [(14)C]MNTX bromide in mice, rats, dogs, and humans after intravenous administration. Separation and identification of plasma and urinary MNTX metabolites was achieved by high-performance liquid chromatography-radioactivity detection and liquid chromatography/mass spectrometry.

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A series of 3-(arylamino)-3-phenylpropan-2-olamines was prepared and screened for their ability to inhibit monoamine reuptake. A number of analogues displayed significant dual norepinephrine and serotonin reuptake inhibition. Compounds in this class exhibited minimal affinity for the dopamine transporter.

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An efficient and mild method to couple aryl bromides and activated non-allylic alcohols in a Heck reaction with tandem isomerization to selectively afford high yields of 1,5-diarylalkan-1-ones has been developed. Mechanistic insight was gained through NMR studies of products derived from deuterium-labeled intermediates.

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The effectiveness of precursor-directed biosynthesis to generate diazepinomicin (1) analogues with varied ring-A substitutents was investigated by feeding commercially available, potential ring-A precursors such as fluorinated tryptophans, halogenated anthranilates, and various substituted indoles into growing actinomycete culture DPJ15 (genus Micromonospora). Two new monofluorinated diazepinomicin analogues (2 and 3) were identified and characterized by spectroscopic methods. Both derivatives showed modest antibacterial activity against the Gram-positive coccus Staphylococcus aureus with MIC values in the range 8-32 microg/mL.

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The diphenylsulfonyl sulfonamide scaffold represented by 1 (WAY-316606) are small molecule inhibitors of the secreted protein sFRP-1, an endogenous antagonist of the secreted glycoprotein Wnt. Modulators of the Wnt pathway have been proposed as anabolic agents for the treatment of osteoporosis or other bone-related disorders. Details of the structure-activity relationships and biological activity from the first structural class of this scaffold will be discussed.

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2-Trifluoromethyl-4-aminobenzimidazoles were previously identified by screening to be active antagonists of the gonadotropin releasing hormone receptor (GnRH-R). Structure activity relationships and diversity oriented synthesis are shown here in greater detail. 2-Substituted benzimidazoles were synthesized in parallel by the coupling of carboxylic acids with a latent intermediate diamine monomer to yield the desired benzimidazoles in fair yields.

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Reaction of (S)- or (R)-3-aminoquinuclidine with 2-chloropyrimidine or 2-bromopyrimidine led to an unexpected formation of both cis- and trans-octahydropyrrolo [2,3]pyridine derivatives. A single-step synthesis of two of the four stereoisomers of these octahydropyrrolo[2,3]pyridine derivatives provides a convenient way of generating stereochemically defined isomers. Optimization of reaction conditions was carried out by (1)H NMR monitoring.

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Glucuronidation, which may take place on the phenolic hydroxyl and carboxyl groups, is a major pathway of metabolism for thyroxine (T4) and triiodothyronine (T3). In this study, a liquid chromatography/mass spectrometry (LC/MS) method was developed to separate phenolic and acyl glucuronides of T4 and T3. The method was used to collect the phenolic glucuronide of T4 for definitive characterization by NMR and to determine effects of incubation pH, species differences, and human UDP-glucuronosyltransferases (UGTs) involved in the formation of the glucuronides.

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The application of Chiral Technology, or the (extensive) use of techniques or tools for the determination of absolute stereochemistry and the enantiomeric or chiral separation of racemic small molecule potential lead compounds, has been critical to successfully discovering and developing chiral drugs in the pharmaceutical industry. This has been due to the rapid increase over the past 10-15 years in potential drug candidates containing one or more asymmetric centers. Based on the experiences of one pharmaceutical company, a summary of the establishment of a Chiral Technology toolbox, including the implementation of known tools as well as the design, development, and implementation of new Chiral Technology tools, is provided.

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The first efficient and regioselective palladium-catalyzed cyclization of internal alkynes and 2-amino-3-iodoacrylates to give moderate to excellent yields of highly functionalized pyrroles has been developed. This approach is applicable to a range of alkynes and affords the deacylated pyrrole under reaction conditions for most substrates. [reaction: see text]

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In this work, we describe an NMR-based method that utilizes an orientation media composed of the chiral polypeptide liquid crystal poly-gamma-benzyl-L-glutamate (PBLG) dissolved in CDCl(3), to measure the (1)H-(1)H, (1)H-(13)C and (13)C-(13)C residual dipolar couplings (RDCs) of (R) and (S)-ibuprofen. Calculated RDCs, obtained from the lowest energy conformers, are then compared with the experimentally measured RDCs to predict the stereochemistry of each enantiomer. Excellent agreement between calculated and experimental RDCs was found when the lowest energy structure of each enantiomer, obtained in a simulated PBLG/CDCl(3) environment, was used to back-calculate the RDCs.

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Burn trauma triggers hypermetabolism and muscle wasting via increased cellular protein degradation and apoptosis. Proton nuclear magnetic resonance (1H NMR) spectroscopy can detect mobile lipids in vivo. To examine the local effects of burn in skeletal muscle, we performed in vivo 1H NMR on mice 3 days after burn trauma; and ex vivo, high-resolution, magic angle spinning (1)H NMR on intact excised mouse muscle samples before and 1 and 3 days after burn.

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A high-resolution, phase-sensitive, natural abundance F2-coupled 1H-13C HSQC (F2HSQC) NMR experiment was developed to measure simultaneously both (n)D(HH) and 1D(CH) residual dipolar couplings (RDCs) of small molecules present in a chiral polypeptide liquid crystal solvent system composed of poly-gamma-benzyl-L-glutamate (PBLG) in CDCl3. Because this is an indirect-detection NMR experiment, the relatively small amount of sample (7.5 mg in this study) and short acquisition times (5 h) that are required make this HSQC experiment well suited for samples that are either limited in solubility or in quantity or require short analysis times.

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