Pat N. Confalone

Discovery and mode of action of afoxolaner, a new isoxazoline parasiticide for dogs

Afoxolaner is an isoxazoline compound characterized by a good safety profile and extended effectiveness against fleas and ticks on dogs following a single oral administration. In vitro membrane feeding assay data and in vivo pharmacokinetic studies in dogs established an afoxolaner blood concentration of 0.1-0.2 μg/ml to be effective against both fleas (Ctenocephalides felis) and ticks (Dermacentor variabilis). Pharmacokinetic profiles in dogs following a 2.5mg/kg oral dosage demonstrated uniform and predictable afoxolaner plasma concentrations above threshold levels required for efficacy for more than one month. Dose ranging and a 5-month multi-dose experimental study in dogs, established that the 2.5mg/kg oral dosage was highly effective against fleas and ticks, and produced predictable and reproducible pharmacokinetics following repeated dosing. Mode of action studies showed that afoxolaner blocked native and expressed insect GABA-gated chloride channels with nanomolar potency. Afoxolaner has comparable potency between wild type channels and channels possessing the A302S (resistance-to-dieldrin) mutation. Lack of cyclodiene cross-resistance for afoxolaner was confirmed in comparative Drosophila toxicity studies, and it is concluded that afoxolaner blocked GABA-gated chloride channels via a site distinct from the cyclodienes.

A short and stereospecific synthesis of (±)-α-lycorane

Abstract (±)-α-Lycorane (4) has been synthesized stereospecifically in five steps from commercially available 3,4-(methylenedioxy)phenylacetonitrile (7). The key step involves an intramolecular unstabilized iminium ylide-olefin [3+2] cyclo addition reaction 6 → 9.

A new asymmetric 1,4-addition method: application to the synthesis of the HIV non-nucleoside reverse transcriptase inhibitor DPC 961

Abstract The asymmetric synthesis of the HIV non-nucleoside reverse transcriptase inhibitor (NNRTI) DPC 961 is achieved in three steps with an overall yield of >55%. The asymmetry is induced by the chiral auxiliary (R)-(+)-α-methylbenzylamine, utilizing a new asymmetric 1,4-addition protocol.

The preparation of the AZA-spirobicyclic system of discorhabdin C via an intramolecular phenolate alkylation

A model study designed for the synthesis of the discorhabdin alkaloids is presented. The key reaction is the intramolecular para-phenolate alkylation of the mesyloxy aminonaphthoquinone 10 to afford the target tetracyclic system 11.

Model studies for the total synthesis of the maytansinoids based on the intramolecular nitrile oxide-olefin [3+2] cycloaddition reaction

Abstract The macrocyclization of the olefinic nitrile oxide 30 to the ansa-macrolide skeleton 37 , a model for a novel approach to the maytansinoids, is described.

Intramolecular [3+2] cycloadditions of functionalized azomethine ylides

Abstract The use of dithiane chemistry to synthesize functionalized azomethine ylides which are then employed in [3+2] cycloaddition chemistry is described. The advantages of this methodology as well as an approach to the lycorenine alkaloid system are presented.

A new and practical synthesis of vinyl dichlorides via a non-Wittig-type approach

Abstract A practical approach for the conversion of aldehydes to vinyl dichlorides has been developed. These are three-step, one-pot reactions involving the formation of trichlorocarbinol by treatment of aldehydes with trichloroacetic acid and sodium trichloroacetate followed by in situ protection and elimination reactions to form the desired vinyl dichlorides in 85 to 95% yields.

The intramolecular nitrile oxide-olefin [3+2] cycloaddition route to the maytansinoids

Abstract The macrocyclization of the olefinic nitrile oxide 24 to the ansa-macrolide skeleton 26, a model for a novel approach to the maytansinoids, is described.

Mostueine: synthesis and structure revision

Abstract A total synthesis of mostueine (1) based upon the intramolecular alkylation of the indole nitrogen is described. A revision of the reported sterochemistry of mostueine to 3SR , 19RS as elucidated by synthesis and NOE data is disclosed.

Chemoselective allylic addition of allyltrichlorosilane to α-oxocarboxylic acids: synthesis of tertiary α-hydroxy carboxylic acids

Abstract Allyltrichlorosilane can add to α-oxocarboxylic acids in the presence of DMF and HMPA. The α-carboxylic substituent exerts a remarkable neighboring group effect on the reaction. The reaction presumably proceeds in an intramolecular fashion through a ‘rigid’ bicyclic transition state assembly involving a hypervalent silicate species, which produces the chemoselectivity approaching 100%.