Dane Goff

The synthesis of 2-oxopiperazines by intramolecular Michael addition on solid support

Abstract Attempted cyclopropanation of unsaturated peptoids on solid support led to the discovery of a facile method for generating libraries of constrained cyclic peptoids.

The preparation of 2,4-disubstituted thiazoles on solid support

Abstract Conversion of a nitrile to a thioamide on solid support has been achieved. This permits an efficient synthesis of 2,4-disubstituted thiazoles.

A peptoid based synthesis of di- and tri-substituted 2-oxopiperazines on solid support

Abstract 2-Oxopiperazines containing up to five variable ring substituents can be obtained by the tandem SN2/Michael addition of amines to unsaturated peptoids on solid support.

Nmr Structural Characterization of Oligo-N-Substituted Glycine Lead Compounds from a Combinatorial Library

Synthesis and screening of combinatorial librariesfor pharmaceutical lead discovery is a rapidlyexpanding field. Oligo-N-substituted glycines (NSGs)were one of the earliest sources of moleculardiversity in combinatorial libraries. In one of thefirst demonstrations of the power of combinatorialchemistry, two NSG trimers, CHIR-2279 and CHIR-4531,were identified as nM ligands for two 7-transmembraneG-protein-coupled receptors. The NMR characterizationof these two lead compounds was undertaken to verifycovalent connectivity and to determine solutionconformations, if any. The sequential chemical shiftassignments were performed using a new strategy forassigning 1H and 13C resonances of NSGs. The conformational preferences were then determined inboth an aqueous co-solvent system and an organicsolvent to probe the effects of hydrophobic collapse. NSGs are expected to be more flexible than peptidesdue to the tertiary amide, with both cis andtrans amide bond conformations being accessible. Solution NMR studies indicate that although CHIR-2279and CHIR-4531 have identical backbones and termini,and very similar side chains, they do not display thesame solution conformational characteristics.

COMBINATORIAL SYNTHESIS OF INDOLIZINES ON SOLID SUPPORT

Abstract A solid phase synthesis of trisubstituted aromatic indolizines utilizing a formal [3+2] dipolar cycloaddition of a resin-bound pyridinium salt with chalcones followed by oxidation has been achieved. The utility of this procedure for the synthesis of combinatorial libraries is also demonstrated.

The synthesis of 2-imldazolidones on solid support by tandem aminoacylation/Michael addition

Abstract Reaction of isocyanates with unsaturated amines bound to a solid support can lead either to 2-imidazolidones or 2-iminooxazolidinones depending on conditions. The imidazolidones are a useful new framework for combinatorial library synthesis.

Synthesis, Binding Mode, and Antihyperglycemic Activity of Potent and Selective (5-Imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine Inhibitors of Glycogen Synthase Kinase 3.

In an effort to identify new antidiabetic agents, we have discovered a novel family of (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine analogues which are inhibitors of human glycogen synthase kinase 3 (GSK3). We developed efficient synthetic routes to explore a wide variety of substitution patterns and convergently access a diverse array of analogues. Compound 1 (CHIR-911, CT-99021, or CHIR-73911) emerged from an exploration of heterocycles at the C-5 position, phenyl groups at C-4, and a variety of differently substituted linker and aminopyridine moieties attached at the C-2 position. These compounds exhibited GSK3 IC50s in the low nanomolar range and excellent selectivity. They activate glycogen synthase in insulin receptor-expressing CHO-IR cells and primary rat hepatocytes. Evaluation of lead compounds 1 and 2 (CHIR-611 or CT-98014) in rodent models of type 2 diabetes revealed that single oral doses lowered hyperglycemia within 60 min, enhanced insulin-stimulated glucose transport, and improved glucose disposal without increasing insulin levels.