Discovery and development of veterinary antiparasitic drugs: past, present and future.

Despite investment in programs to manage the development of resistance to existing agents, this continues to drive the need for discovery of novel antiparasitic agents for veterinary medicine. Historically, antiparasitic drug discovery was driven by empirical screening, but technological advances have lead to an increased focus on mechanism-based approaches to drug discovery and this is projected to increase as our capabilities advance to improve both the throughput of assays and the quality of data generated. Investment in the development of combination products with novel agents is increasing and, despite regulatory hurdles in some regions, efforts to globally harmonize regulations will aid in delivering safe, efficacious drugs to help in resistance management and integrated parasite control programs.

Synthesis and SAR comparison of regioisomeric aryl naphthyridines as potent mGlu5 receptor antagonists.

We describe three novel regioisomeric series of aryl naphthyridine analogs, which are potent antagonists of the Class III GPCR mGlu5 receptor. The synthesis and in vitro and in vivo pharmacological activities of these analogs are discussed.

Synthesis and SAR of 2-aryl pyrido[2,3-d]pyrimidines as potent mGlu5 receptor antagonists.

A novel series of potent 2-aryl pyrido[2,3-d]pyrimidine mGlu5 receptor antagonists are described. The synthesis and pharmacological activities of these analogs are discussed.

Rational design of 7-arylquinolines as non-competitive metabotropic glutamate receptor subtype 5 antagonists.

Rational replacement of the alkyne linker of mGluR5 antagonist MPEP gave 7-arylquinolines. SAR optimization gave an orally active compound with high affinity for the MPEP binding site.

Convergent, parallel synthesis of a series of beta-substituted 1,2,4-oxadiazole butanoic acids as potent and selective alpha(v)beta3 receptor antagonists.

We describe a series of 1,2,4-oxadiazoles, which are potent antagonists of the integrin alpha(v)beta3 and, in addition, show selectivity relative to the other beta3 integrin alpha(IIb)beta3. In whole cells, the majority of these analogs also demonstrated modest selectivity against other alpha(v) integrins such as alpha(v)beta1 and alpha(v)beta6.

Synthesis of 2,5-thiazole butanoic acids as potent and selective alpha(v)beta3 integrin receptor antagonists with improved oral pharmacokinetic properties.

We describe a series of 2,5 thiazole containing compounds, which are potent antagonists of the integrin alpha(v)beta3 and show selectivity relative to the other integrins, such as alpha(IIb)beta3 and alpha(v)beta6. These analogs were demonstrated to have high bioavailability relative to other relative heterocyclic analogs.

First asymmetric total synthesis of (+)-sparteine.

[reaction: see text] The total synthesis of (+)-sparteine was accomplished from 2,5-norbornadione in 15 steps and 15.7% overall yield. The key steps were two ring-expansion reactions, one involving an intramolecular Schmidt reaction and one using a novel variant of the photo-Beckmann rearrangement.