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.

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.

Comparative disposition and metabolism of paraherquamide in sheep, gerbils, and dogs.

The disposition and metabolism of paraherquamide (PHQ), a potent and broad-spectrum anthelminthic, were examined in sheep, dogs, and gerbils. The metabolism of PHQ in these species was extensive and marked by significant species differences both in vitro and in vivo. In sheep and gerbils, PHQ metabolism occurs mainly at the pyrrolidine moiety, generating several metabolites that, for the most part, retained nematodicidal activity in vitro.

Isolation and insecticidal/anthelmintic activity of xanthonol, a novel bis-xanthone, from a non-sporulating fungal species.

Xanthonol, a novel dimeric xanthone, was isolated from a fermentation broth of a non-sporulating fungal species using Sephadex LH20 followed by HPLC and the structure elucidated by spectral analysis. Xanthonol exhibited insecticidal and anthelmintic activities against larvae of Lucilia sericata, Aedes aegypti, and Haemonchus contortus with LD90 of 33, 8, and 50 microg/ml, respectively.

p38 MAP kinase inhibitors: metabolically stabilized piperidine-substituted quinolinones and naphthyridinones.

Quinolinones and naphthyridinones with C7 N-t-butyl piperidine substituents were found to be potent p38 MAP kinase inhibitors. These compounds significantly suppress TNF-alpha release in both cellular and LPS-stimulated whole blood assays. They also displayed excellent PK profiles across three animal species.

Rediocides B-E, potent insecticides from Trigonostemon reidioides.

Four new congeners, rediocides B-E (2-5), of the previously reported rediocide A (1) were isolated from a methanol extract of the roots of the plant Trigonostemon reidioides. The structures of these minor analogues were elucidated by comparison of their NMR and mass spectral data with those of rediocide A and confirmed by extensive 2D NMR spectral analysis. They all possess potent activity against fleas (Ctenocephalides felis) in an artificial membrane feeding system and exhibited LD(90) values ranging from 0.

Nodulisporic acids C, C1, and C2: a series of D-ring-opened nodulisporic acids from the fungus Nodulisporium sp.

Nodulisporic acids C (4a), C1 (5a), and C2 (6a), a series of D-ring-opened nodulisporic acids, were isolated from fermentations of a mutant culture of Nodulisporium sp. MF5954. Nodulisporic acid C, the most potent of the three, showed good activity against fleas with an LD90 of 10 micro g/mL.

Hybrid-designed inhibitors of p38 MAP kinase utilizing N-arylpyridazinones.

Imidazo[1,2-a]pyridyl N-arylpyridazinones were hybridized from the classic pyridinylimidazoles and the more recent dual hydrogen bond acceptors, resulting in a new structural class of selective p38 MAP kinase inhibitors.

Amphidial structure of ivermectin-resistant and susceptible laboratory and field strains of Haemonchus contortus.

The development of anthelmintic resistance by nematode parasites is a growing problem for veterinarians, pet owners, and producers. The intensive use of the macrocyclic lactones for the treatment of a variety of parasitic diseases has hastened the development of resistance to this family of parasiticides. As a result, resistance to ivermectin, moxidectin, nemadectin, and doramectin by Haemonchus contortus has been documented throughout the world.

Nodulisporic acid side-chain modifications: access to the 2", 3", 4", and 6" registers.

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 Delta(2",3")-olefin isomer 2b was obtained.

Nodulisporic acid B, B1, and B2: a series of 1'-deoxy-nodulisporic acids from Nodulisporium sp.

During the re-isolation of the lead compound nodulisporic acid A (1a) and targeted chemical screening for related compounds, we discovered a series of 1'-deoxy congeners named herein nodulisporic acids B (1b), B1 (2b), and B2 (3b). In comparison with nodulisporic acid A, these compounds were less active and were chemically unstable resulting into formation of delta23 dehydro derivatives. Therefore, these compounds were stabilized and isolated as sodium salts and methyl ester.

Side-chain homologation of nodulisporic acid: synthesis of potent new dienyl derivatives.

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 activity.

Nodulisporic acid: its chemistry and biology.

The discovery of the natural product nodulisporic acid A (NsA A) and its potent, systemic insecticidal activity at Merck Research Laboratories in 1992 stimulated intense scientific scrutiny. Interest in this new class of indole diterpenes led to extensive delineation of its properties, both chemical and biological. Synthetic modification of NsA A served to identify its pharmacologically permissive and non-permissive regions, produced semisynthetic derivatives with enhanced adulticidal flea efficacy (both in vitro and in vivo), and provided useful tools to support biological studies.