No abstract

We report the discovery of potent benzamide inhibitors of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1). The optimization and correlation of in vitro and in vivo metabolic stability will be described. Through modifications to our initial lead 2, we discovered pyridyl compound 13. This compound has a favorable pharmacokinetic profile across three species and showed a dose-dependent decrease in adipose 11beta-HSD1 activity in a monkey ex vivo pharmacodynamic model.

Small molecule TRPV1 antagonists have been a recent focus in the search for pain treatment agents. We herein describe a practical and scalable synthesis of AMG 628 (1), a bis-substituted pyrimidine derivative that was identified as a highly efficacious agent, suitable for clinical development. Highlights of our approach include a practical route to a substituted benzothiazole, a scalable synthesis of an enantiopure piperazine fragment, and identification of conditions for selective coupling reactions on 2,6-dichloropyrimidine, to access the active pharmaceutical ingredient in high purity and overall yield.

A diastereoselective palladium-catalyzed arylation of 4-substituted cyclohexyl esters has been developed. The reaction proceeds at room temperature in the presence of [(t-Bu3P)PdBr]2 providing products in up to 37:1 dr.

Trituration and crystallization are essential techniques for purification of intermediates and drug substances in pharmaceutical process development. Traditionally, identifying the optimal solvent conditions for impurity rejection adopts an empirical approach that can be a time and material consuming process. On the basis of thermodynamic considerations for optimizing the purity and the yield of the crystal product, it is necessary to conduct screening experiments with the crude product in different solvents including mixtures of solvents. In this report, we describe the development and the implementation of a high-throughput screening workflow in a 96-well array format for identifying the optimal purification conditions. The impure samples were first triturated at room temperature and subsequently subjected to a thermal cycle in 96 unique solvents or solvent mixtures at a volume of 0.6 mL per well. The compound solubility and the impurity profiles of both supernatant and recovered solid were analyzed by HPLC. Using a mixture of acetylsalicylic acid containing salicylic acid as the impurity, we investigated the effects of material loading per sample and impurity level on product purity/solubility under both screening and scale-up conditions and evaluated the thermodynamic behavior of product-impurity-solvent interactions based on an isothermal ternary phase diagram. During a further case study, a binary solvent system was identified, and the synergistic effect of binary components was demonstrated for purification of an Amgen compound containing three impurities. This high-throughput screening approach is valuable as an integrated part of process development to identify the thermodynamically favored solvent conditions for purification of pharmaceutical compounds.