Stephen W. Kaldor

Use of solid supported nucleophiles and electrophiles for the purification of non-peptide small molecule libraries

Abstract Solid supported nucleophiles and electrophiles are employed to expedite the work-up and purification of a variety of amine alkylations acylacylations. These solid suported scavengers are particularly advantageous for the construction of non-peptide libraries in a parallel array format.

5-HT1F receptor agonists inhibit neurogenic dural inflammation in guinea pigs.

THE serotonin (5-HT) receptor subtype mediating inhibition of neurogenic dural inflammation in guinea pigs was investigated using a series of serotonin agonists with differing affinities for the 5-HT1B, 5-HT1D and 5-HT1F receptors. When agonist potencies for inhibiting neurogenic inflammation were compared with affinities for these receptor subtypes, a significant positive correlation was seen only with the 5-HT1F receptor. The potency of agonists in inhibiting adenylate cyclase in cells transfected with human 5-HT1F receptor was also highly correlated with their potency in the animal model of migraine. In situ hybridization demonstrated 5-HT1F receptor mRNA in guinea pig trigeminal ganglion neurons. These data suggest that the 5-HT1F receptor is a rational target for migraine therapeutics.

Rapid purification of small molecule libraries by ion exchange chromatography

Abstract Amines and acylated amines are synthesized in traditional solution phase reactions, then rapidly purified by ion exchange chromatography to yield pure products. In some instances, impurities devoid of ionizable functionality can be covalently modified prior to purification. The generic purification sequence is applicable to a variety of reactions, and is amenable to automation with commercially available equipment.

Combinatorial chemistry using polymer-supported reagents

During the past several years, the field of combinatorial chemistry has expanded to include not only solid- and solution-phase methods for expedited compound synthesis, but also hybrid approaches that span these two extremes. In particular, polymer-supported reagents have emerged as useful combinatorial chemistry tools for the discovery and optimization of new pharmaceutical leads.

A mild, osmium tetraoxide-catalyzed method for the oxidation of sulfides to sulfones

Abstract Osmium tetraoxide has been demonstrated to be a highly efficient catalyst for the chemoselective oxidation of a variety of sulfides to the corresponding sulfones. Tertiary amine catalysis appears to play a key role in the reaction.

DISCOVERY OF ANTIRHINOVIRAL LEADS BY SCREENING A COMBINATORIAL LIBRARY OF UREAS PREPARED USING COVALENT SCAVENGERS

Abstract Solution phase parallel synthesis of equimolar mixtures of ureas was accomplished using a solid-supported “covalent scavenger” (aminomethylpolystyrene) to remove isocyanate impurities. Screening of these purified mixtures for antirhinoviral activity in a whole cell assay and subsequent deconvolution of hit mixtures afforded novel antirhinoviral agents with low cytotoxicities.

Glutamine-derived aldehydes for the inhibition of human rhinovirus 3C protease

Peptide aldehydes have been synthesized and evaluated as inhibitors of human rhinovirus 3C protease. Those inhibitors containing a C-terminal glutamine aldehyde were prepared using newly developed methodology involving reduction of the corresponding glutarimide, which can be easily prepared from N-protected glutamine. Low molecular weight (<500) compounds with low to submicromolar inhibitory activity in both isolated enzyme and in vitro translation assays have been identified.

Solid phase synthesis of urea libraries using a diversifiable thiophenoxy carbonyl linker

Abstract A method for the solid phase synthesis of urea libraries from primary and secondary amines is described which utilizes a thiophenoxy carbonyl linker. Sequential release of different urea products from a common batch of resin using a “milking” procedure has also been accomplished.

New dipeptide isosteres useful for the inhibition of HIV-1 protease

Abstract A family of readily accessible Phe-Pro mimics has been devised in which ortho-substituted benzamides serve as proline surrogates. When suitably functionalized, these dipeptide isosteres afford potent inhibitors of HIV-1 protease which are also effective in whole cell antiviral assays.

Structure-based drug design of nonpeptidic P2 substituents for HIV-1 protease inhibitors

Abstract The cocrystal structures of LY289612 and LY297135 were used as a starting point in the design of nonpeptidic HIV-1 protease inhibitors. This report details the discovery of a series of novel aromatic P 2 replacement groups. The 3-hydroxy-2-methyl benzoic acid group, discovered in AG1254, was incorporated into the hydroxyethyl amine series to produce the potent antiviral compound (LY309391/ AG1310).