Christopher Ronald Sarko

A new class of 5-HT2B antagonists possesses favorable potency, selectivity, and rat pharmacokinetic properties.

We have been exploring the potential of 5-HT(2B) antagonists as a therapy for chronic heart failure. To assess the potential of this therapeutic approach, we sought compounds possessing the following attributes: (a) potent and selective antagonism of the 5-HT(2B) receptor, (b) low impact of serum proteins on potency, and (c) desirable pharmacokinetic properties. This Letter describes our investigation of a biphenyl benzimidazole class of compounds that resulted in 5-HT(2B) antagonists possessing the above attributes. Improving potency in a human serum albumin shift assay proved to be the most significant SAR discovery.

Microwave-assisted synthesis of a [3+2] cycloaddition library

Abstract A novel method for the synthesis of a library of substituted prolines utilizing microwave-assisted synthesis is described. The process involves rapid microwave irradiation of α-aminoesters and aldehydes to generate imines followed by the addition of a dipolarophile and subsequent irradiation to produce the [3+2] cycloadducts. The decrease in reaction time afforded by microwave irradiation allowed for the production of an 800-membered solution-phase library in twofold less time than by traditional thermal methods. These products were purified by solid-supported reagent scavenging to furnish the desired products in high yields and purity.

Microwave-assisted synthesis of 2-aminoquinolines

An improved method for the synthesis of 2-aminoquinolines utilizing microwave-assisted synthesis is described. The process involves rapid microwave irradiation of secondary amines and aldehydes to form enamines followed by the addition of 2-azidobenzophenones with subsequent irradiation to produce the 2-aminoquinoline derivatives. Purification of the products is accomplished in a streamlined manner using solid-phase extraction techniques to produce the desired products in high yields and purity.

2 – Analysis of a Combinatorial Library Synthesized Using a Split-and-Pool Irori MicroKan Method for Development and Production

Publisher Summary This chapter discusses the analytical methods and techniques used in the combinatorial chemistry group for 100% quality control (QC) analysis during the development and production of the libraries. It also describes automated solid phase extraction (SPE) methods as high throughput purification of combinatorial libraries. These multidimensional libraries can be quickly assembled from small sets of reagents producing very large libraries. Chemical tagging techniques in split-and-pool synthesis prevents the time-consuming deconvolution steps required in early syntheses; however, chemical tags may not be compatible with all relevant chemistries. An alternative for this is radio frequency (RF) tagging microchips. Incorporation of a discrete tag allows for individual compound generation while tracking compound identity. Such a synthetic vessel is the Irori MicroKan. This vessel can hold 30 mg of solid support and encase the RF tag, thus combining identity and individuality of the compounds. Combinatorial libraries generated by the Irori MicroKan method benefit from the split-and-pool synthesis on solid support and from the parallel synthesis technique producing one target compound per well without the need for deconvolution. Employing efficient and effective software is essential for the massive analytical data processing and presentation. New technologies to enhance the purity and quality of the library, including culling and reformatting procedures, high throughput chromatographic purification, and supercritical fluid chromatography (SFC), are continuously explored.