George Philip Lahm

New and selective ryanodine receptor activators for insect control

Diamide insecticides have emerged as one of the most promising new classes of insecticide chemistry owing to their excellent insecticidal efficacy and high margins of mammalian safety. Chlorantraniliprole and flubendiamide, the first two insecticides from this class, demonstrate exceptional activity across a broad range of pests in the order Lepidoptera. This chemistry has been confirmed to control insects via activation of ryanodine receptors which leads to uncontrolled calcium release in muscle. The high levels of mammalian safety are attributed to a strong selectivity for insect over mammalian receptors.

The discovery of indoxacarb: oxadiazines as a new class of pyrazoline-type insecticides†

The evolution of the insecticidal pyrazoline moiety that was originally discovered in 1972 has led to the discovery of a new crop insecticide, indoxacarb, which is the first commercialized pyrazoline-type sodium-channel blocker. Both monocyclic and fused-tricyclic pyrazolines and pyridazines, as well as structurally related semicarbazones were examined prior to the discovery of analogous tricyclic oxadiazines which had similarly high activity as well as favorable environmental dissipation rates and low toxicity to non-target organisms. The eventual leading candidate, DPX-JW062, was originally obtained as a racemic molecule, but a chiral synthesis was developed which produces material that is 50% ee in the insecticidal (+)-S-enantiomer (DPX-MP062, indoxacarb).

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.

Discovery of cyantraniliprole, a potent and selective anthranilic diamide ryanodine receptor activator with cross-spectrum insecticidal activity

Anthranilic diamides are an exceptionally active class of insect control chemistry that selectively activates insect ryanodine receptors causing mortality from uncontrolled release of calcium ion stores in muscle cells. Work in this area led to the successful commercialization of chlorantraniliprole for control of Lepidoptera and other insect pests at very low application rates. In search of lower logP analogs with improved plant systemic properties, exploration of cyano-substituted anthranilic diamides culminated in the discovery of a second product candidate, cyantraniliprole, having excellent activity against a wide range of pests from multiple insect orders. Here we report on the chemistry, biology and structure-activity trends for a series of cyanoanthranilic diamides from which cyantraniliprole was selected for commercial development.

Synthesis of insecticidal fluorinated anthranilic diamides

A series of highly active fluorinated anthranilic diamide insecticides have been prepared and their biological activity assessed on two aphid species in the search for systemically active compounds that control Hemiptera. In addition, we have demonstrated a new synthesis of N-aryl 3-fluoropyrazoles.

4-Azolylphenyl isoxazoline insecticides acting at the GABA gated chloride channel.

Isoxazoline insecticides have been shown to be potent blockers of insect GABA receptors with excellent activity on a broad pest range, including Lepidoptera and Hemiptera. Herein we report on the synthesis, biological activity and mode-of-action for a class of 4-heterocyclic aryl isoxazoline insecticides.

Insecticidal quinoline and isoquinoline isoxazolines

A series of quinoline and isoquinoline isoxazolines have been designed as pesticides for crop protection. Herein we reported the chemical synthesis, biological activity and structure-activity relationships. The isoquinoline derivative, such as 3i, is discovered as potent new class of isoxazoline insecticide which is competitive with commercial insecticide Indoxacarb.

A retrospective look at anthranilic diamide insecticides: discovery and lead optimization to chlorantraniliprole and cyantraniliprole

Anthranilic diamides are an important commercial synthetic class of insecticides (IRAC Group 28) that bind to the ryanodine receptor with selective potency against insect versus mammalian forms of the receptor. The first commercialized diamide, chlorantraniliprole, has exceptional activity against lepidopteran pests. The second anthranilamide product, cyantraniliprole, has excellent cross-spectrum activity against a range of insect orders, including both lepidopteran and hemipteran pests. Here, a retrospective look is presented on the discovery of the class, along with chemistry highlights of the lead evolution to both products.

Mesoionic insecticides: A novel class of insecticides that modulate nicotinic acetylcholine receptors

BACKGROUND As the world population grows towards 9 billion by 2050, it is projected that food production will need to increase by 60%. A critical part of this growth includes the safe and effective use of insecticides to reduce the estimated 20-49% loss of global crop yields owing to pests. The development of new insecticides will help to sustain this protection and overcome insecticide resistance. RESULTS A novel class of mesoionic compounds has been discovered, with exceptional insecticidal activity on a range of Hemiptera and Lepidoptera. These compounds bind to the orthosteric site of the nicotinic acetylcholine receptor and result in a highly potent inhibitory action at the receptor with minimal agonism. The synthesis, biological activity, optimization and mode of action will be discussed. CONCLUSION Triflumezopyrim insect control will provide a powerful tool for control of hopper species in rice throughout Asia. Dicloromezotiaz can provide a useful control tool for lepidopteran pests, with an underexploited mode of action among these pests.

Mesoionic pyrido[1,2-a]pyrimidinones: A novel class of insecticides inhibiting nicotinic acetylcholine receptors

A novel class of mesoionic pyrido[1,2-a]pyrimidinones has been discovered with exceptional insecticidal activity controlling a number of insect species, particularly hemiptera and lepidoptera. Mode-of-action studies showed that they act on nicotinic acetylcholine receptors (nAChRs) primarily as inhibitors. Here we report the discovery, evolution, and preparation of this class of chemistry. Our efforts in structure-activity relationship elucidation and biological activity evaluation are also presented.