Thomas L. Shih

L-770,644 : A potent and selective human β3 adrenergic receptor agonist with improved oral bioavailability

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 evaluation.

Discovery of novel avermectins with unprecedented insecticidal activity

A new class of insecticidal and antiparasitic agents, 4″-amino-4′-deoxy avermectins, has been developed by chemical modification of avermectin B1. The most effective of these compounds are 1500-fold more potent than avermectin B1 (abamectin) against the beet armywormSpodoptera exigua and show similar potency against other lepidopteran larvae.

The total synthesis of argiopine (argiotoxin-636)

Abstract The total synthesis of a constituent of spider venom with reported glutamate receptor channel activity is described.

4 -DEOXY-4 -AMINOAVERMECTINS WITH POTENT BROAD SPECTRUM ANTIPARASITIC ACTIVITIES

Abstract Reductive amination of 4″-oxo-5-O-tert-butyldimethylsilyl-avermectins with sodium cyanoborohydride and ammonium acetate gave an epimeric mixture of 4″-deoxy-4″-amino analogs with the epimeric, axial 4″-β-amino derivative as the major component. Acylation of the amino substituent gave highly active broad spectrum antiparasitic compounds, as determined in a sheep anthelmintic assay. 4″-Epi-acetylamino-4″-deoxyavermectin B 1 ( 12 ) was selected for further antiparasitic studies and is currently under development as a novel avermectin endectocide.

A wittig approach to novel C24 and C25-substituted avermectins.

Abstract The Wittig condensation of aldehydes 2A and 2B with the appropriate phosphonium ylids under Bestmanns “salt-free” conditions 3 gave the Z-olefin precursors 3A and 3B respectively. Treatment of 3A and 3B with methanolic pyridinium tosylate effected desilylation and intramolecular spiroketalization to generate synthetic avermectins ( 4 ) having the thermodynamic dioxaspirane configuration found in natural avermectins.

Discovery of the Development Candidate N-tert-Butyl Nodulisporamide: A Safe and Efficacious Once Monthly Oral Agent for the Control of Fleas and Ticks on Companion Animals

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 intrinsic systemic potency as well as in a mouse/bedbug assay for systemic efficacy and safety. A cohort of 66 nodulisporamides were selected for evaluation in a dog/flea model; pharmacokinetic analysis correlated plasma levels with flea efficacy. These efforts resulted in the identification of the development candidate N-tert-butyl nodulisporamide (3) as a potent and efficacious once monthly oral agent for the control of fleas and ticks on dogs and cats which was directly compared to the topical agents fipronil and imidacloprid, with favorable results obtained. Multidose studies over 3 months confirmed the in vivo ectoparasiticidal efficacy and established that 3 lacked overt mammalian toxicity. Tissue distribution studies in mice using [(14)C]-labeled 3 indicate that adipose beds serve as ligand depots, contributing to the long terminal half-lives of these compounds.

Rapid pharmacokinetic screening for the selection of new drug discovery candidates using a generic isocratic liquid chromatography–atmospheric pressure ionization tandem mass spectrometry method

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 less for a wide range of compounds. This is a great advantage in new drug discovery where many compounds are analyzed once and eliminated. No time is consumed developing chromatographic conditions for each new compound. The mass spectrometer can be optimized and the samples can be processed and analyzed, all in the same day. Multiple assays can be run consecutively without changing the column or mobile phase between assays.

Argiopine differentiates between vertebrate and invertebrate glutamate binding sites

Abstract The venoms of several species of Araneidae spiders contain components which specifically inhibit the postsynaptic response of cells to glutamate stimulation. Argiopine is the active component identified in the venom of the spider Argiope lobata . Synthetically prepared argiopine is a competitive inhibitor of specific [ 3 H]glutamate binding to membranes prepared from the nematode Caenorhabditis elegans with an inhibition constant of 8 μ M . The in vivo nematocidal activity of argiopine was assessed by incubating C. elegans in various concentrations of the toxin and quantitating its effect on motility. Under these conditions, the ED 50 value for argiopine is 25 μ M . However, argiopine has no inhibitory effect on [ 3 H]glutamate binding to membranes prepared from rat brain. Our results demonstrate that argiopine interacts with a glutamate binding site in C. elegans pharmacologically distinct from that present in mammalian brain tissue.

Reactivity of an epoxy-spiroketal within avermectin B2a

Abstract Interesting reactivities have been observed upon reaction of epoxy-spiroketal 1 with a variety of dimethyl-aluminum sulfides, and are compared with results obtained upon reaction of the same epoxide 1 with diethyl aluminum cyanide. These chemical modifications provide access to novel avermectin B 2a analogs possessing interesting biological properties.

An unusual twist in the synthesis and hydrolysis of the 23,24-epoxide of 22,23-dihydroavermectin B1a

Abstract Treatment of 4″,5-di-O-tert-butyldimethylsilyl(or phenoxyacetyl)-7-O-trimethylsilyl-avermectin B 2a ( 1a,b ) with diethylaminosulfur trifluoride (DAST) at 20AC in dichloromethane resulted in net elimination of water to yield 65% of the 23,24-olefin ( 2a,b ), 5–10% 23-fluoroavermectin derivative ( 3a,b ), and 20–25% of two rearranged products ( 4a,b:5a,b in a 2:1 ratio). The trisubstituted 23,24-olefin ( 2a,b ) was selectively epoxidized with m-chloroperbenzoic acid to give a mixture of alpha ( 6a,b major) and beta ( 7a,b minor) 23,24-epoxides in 64% yield. The acid catalyzed hydrolysis of epoxide 6a,b unexpectedly afforded hemiketal 9a,b as the major product (60%) and the usual 23,24-diol 10a,b as the minor product (6%). Subsequent Ley perruthenate oxidation of 9b produced lactone 13b in 15% yield. Lead tetracetate oxidation of 10a produced the desired cleavage product 14a in 40–50% yield.