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Nodulisporic acid A (1) is a structurally complex fungal metabolite that exhibits systemic efficacy against fleas via modulation of an invertebrate specific glutamate-gated ion channel. In order to identify a nodulisporamide suitable for monthly oral dosing in dogs, a library of 335 nodulisporamides was examined in an artificial flea feeding system for(More)
A number of 3-substituted 1D-myo-inositols were synthesized and evaluated as substrates for phosphatidylinositol synthase and uptake by intact cells. 1D-3-Amino-, -3-chloro-, and -3-(acetylthio)-3-deoxy-myo-inositols were all synthesized by nucleophilic displacement of the 6-O-(trifluoromethyl)sulfonyl group of(More)
L-770,644 (9c) is a potent and selective agonist of the human beta3 adrenergic receptor (EC50 = 13 nM). It shows good oral bioavailability in both dogs and rats (%F = 27), and is a full agonist for glycerolemia in the rhesus monkey (ED50 = 0.21 mg/kg). Based on its desirable in vitro and in vivo properties, L-770,644 was chosen for further preclinical(More)
Medicinal chemistry efforts were initiated to identify the key constituents of the nodulisporic acid A (1) pharmacophore that are integral to its potent insecticidal activity. New semisynthetic derivatives delineated 1 into 'permissive' and 'nonpermissive' regions and led to the discovery of new nodulisporamides with significantly improved flea efficacy.
An efficient synthesis of the truncated 3"-aldehyde (3) from nodulisporic acid A (1) under mild conditions is described. Further oxidation of 3 to 3"-carboxylic acid (4) and its subsequent oxidative degradation produced 1"-aldehyde (5). These new derivatives are versatile intermediates for the preparation of new, side chain modified derivatives of(More)
The effects of two beta(3)-adrenergic receptor agonists, (R)-4-[4-(3-cyclopentylpropyl)-4,5-dihydro-5-oxo-1H-tetrazol-1-yl]-N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]benzenesulfonamide and (R)-N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)- ethyl]amino]ethyl]phenyl]-1-(4-octylthiazol-2-yl)-5-indolinesulfonamide, on indices of metabolic and(More)
A generic isocratic HPLC-APCI-MS-MS method has been developed for the determination of plasma concentrations of bioactive compounds for the selection of potential new drug discovery candidates. A 4.6 x 50 mm cyano phase column eluted with an acetonitrile/water mobile phase containing 20 mM ammonium acetate and 0.4% TFA produces retention times of 1 min or(More)
Efficient routes to access the 2", 3", 4", and 6" registers of the nodulisporic acid (NsA) side chain are disclosed. A mild one-carbon, Ph(2)CdoublebondNCH(2)CtriplebondN mediated homologation of NsA's 3"-aldehyde permitted access to the 4"-register. Curtius reaction of NsA's 3"-acid yielded the corresponding 2"-aldehyde 4 from which the unnatural(More)
A series of new, diene-modified nodulisporic acid analogues (2) bearing diverse functionality at the 3"- and 4"-sites was efficiently prepared from the 3"-aldehyde 3. Biological evaluation of these synthetic nodulisporic acid analogues for systemic flea efficacy identified potent compounds and further clarified the structural requirements for ectoparasite(More)
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