Kyungjin Kim

Preparation of novel 2-(trialkylsilyl)ethyl linkers and first synthesis of Tryprostatin B on solid phase

Abstract Two synthetic methods for novel polymer-supported 2-(trialkylsilyl)ethanol linkers 3 are described. The new silyl linker has been examined as a C-terminal linkage to provide several diketopiperazines. Using this synthetic method, the first solid phase synthesis of Tryprostatin B was accomplished. Several functionalized 2-(trialkylsilyl)ethyl linkers 12 – 17 are synthesized from 2-(trialkylsilyl)ethanol linkers. During the course of preparations, the new silyl linkers proved resistant to various reaction conditions such as basic and moderately acidic media, oxidation, and elevated thermal conditions.

2‐Phenoxy‐nicotinamides are Potent Agonists at the Bile Acid Receptor GPBAR1 (TGR5)

Potency with potential: 2-Phenoxy-nicotinamides were identified as potent agonists at the GPBAR1 receptor, a target in the treatment of obesity, type 2 diabetes and metabolic syndrome. Extensive structure-activity relationship studies supported by homology modeling and docking resulted in the identification of optimized GPBAR1 agonists, potent against both human and mouse receptors, endowed with favorable physicochemical properties and good metabolic stability.

Convenient synthesis of 2,9-disubstituted guanines mediated by solid-supported reagents

A novel application has been developed to separate regioisomers chemoselectively using a solid-supported reagent. An N7/N9 purine regioisomer mixture was purified using aluminum oxide/H+ to provide the N9 isomer selectively as a parallel or high-throughput format (chemoselective high-throughput purification). 2,9-Disubstituted guanines were conveniently prepared by this new method in conjunction with solid-supported reagents.

7-Phenyl-pyrido[2,3-d]pyrimidine-2,4-diamines: novel and highly selective protein tyrosine phosphatase 1B inhibitors.

High throughput screening of the Roche compound collection led to the identification of diaminopyrroloquinazoline series as a novel class of PTP1B inhibitors. Structural modification of diaminopyrroloquinazoline series resulted in pyrido[2,3-d]pyrimidine-2,4-diamine series which was further optimized to give compounds 5 and 24 as potent, selective (except T-cell phosphatase) PTP1B inhibitors with good mouse PK properties.

Potent, selective MCH-1 receptor antagonists.

This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety.

Chemoselective high-throughput purification mediated by solid-supported reagents: its application to the first 6, 9-disubstituted purine library synthesis.

A new application of solid-supported reagents was developed to separate the alkylated N7/N9 regioisomers derived from commercially available 2-amino-6-chloropurine. Simple filtration through an alumina/H+ pad or scavenging by AG/Dowex-50W-X8 resin provides diverse N9 regioisomers selectively in moderate yields with high purities (>90%). This purification method can be conveniently used in a high-throughput format and facilitates the synthesis of a purine library without laborious regioisomer separation and aqueous work-up. The first library synthesis of 6,9-disubstituted purines is reported using the combination of this novel separation method in conjunction with polymer-supported reagents.

Novel polymer-supported 2-(diphenylmethylsilyl)ethoxymethyl chloride (DSEM-Cl) linker.

A synthetic method to prepare a novel polymer-supported 2-(diphenylmethylsilyl)ethoxymethyl chloride (DSEM-Cl) linker and its applications are described.