David J. Nelson

Discovery of Disubstituted Cyclohexanes as a New Class of CC Chemokine Receptor 2 Antagonists

We describe the design, synthesis, and evaluation of novel disubstituted cyclohexanes as potent CCR2 antagonists. Exploratory SAR studies led to the cis-disubstituted derivative 22, which displayed excellent binding affinity for CCR2 (binding IC50 = 5.1 nM) and potent functional antagonism (calcium flux IC50 = 18 nM and chemotaxis IC 50 = 1 nM). Site-directed mutagenesis studies with 22 suggest the compound is binding near the key receptor residue Glu291, however, 22 is not reliant on Glu291 for its binding affinity.

Amide surrogates of matrix metalloproteinase inhibitors : Urea and sulfonamide mimics

Abstract A new method for the synthesis of succinyl sulfinyl chlorides was applied to the preparation of sulfonamide peptide mimics of MMP inhibitors. Sulfonamide mimics were determined to be active against MMPs and represent promising new leads for further optimization. Urea mimics were also prepared and found to be unstable and prone to hydantoin formation in protic media.

Glutamyl-γ-boronate Inhibitors of Bacterial Glu-tRNAGln Amidotransferase

Abstract Analogues of glutamyl-γ-boronate ( 1 ) were synthesized as mechanism-based inhibitors of bacterial Glu-tRNA Gln amidotransferase (Glu-AdT) and were designed to engage a putative catalytic serine nucleophile required for the glutaminase activity of the enzyme. Although 1 provides potent enzyme inhibition, structure–activity studies revealed a narrow range of tolerated chemical changes that maintained activity. Nonetheless, growth inhibition of organisms that require Glu-AdT by the most potent enzyme inhibitors appears to validate mechanism-based inhibitor design of Glu-AdT as an approach to antimicrobial development.

Discovery of a Potent and Orally Bioavailable Dual Antagonist of CC Chemokine Receptors 2 and 5.

We describe the hybridization of our previously reported acyclic and cyclic CC chemokine receptor 2 (CCR2) antagonists to lead to a new series of dual antagonists of CCR2 and CCR5. Installation of a γ-lactam as the spacer group and a quinazoline as a benzamide mimetic improved oral bioavailability markedly. These efforts led to the identification of 13d, a potent and orally bioavailable dual antagonist suitable for use in both murine and monkey models of inflammation.

Potent carboxylate inhibitors of stromelysin containing P2' piperazic acids and P1' biaryl moeities

Abstract Several carboxylate derivatives with variation at the P1′ residue were synthesized and evaluated as stromelysin (MMP-3) inhibitors. Compounds containing a biphenyl moiety at P1′ were found to be potent inhibitors of MMP-3. An X-ray crystal structure of the most potent compound, carboxylate 19, revealed an important interaction between the inhibitors biphenyl and histidine 224 in the S1′ pocket of MMP-3.

Probing the P3′ pocket of stromelysin with piperazic acid analogs

Abstract The preparation and SAR of several piperazic acid-based stromelysin (MMP-3) inhibitors is presented. The standard P3′ methyl amide substituent can be replaced by other carboxy based substituents and maintain good binding affinity. Removal of a hydrogen-bond acceptor results in a 30-fold decrease in activity.

The synthesis of pyrimidineisothiazolones. The effect of temperature on the addition of aryl amines to functionalized pyrimidines.

A new synthesis for the hither-to-unknown pyrimidine isothiazolones 1 and 2 is detailed. The low tempetature selectivity of amine nucleophiles on 6-chloropyrimidine-5-acylbromides (12) for the acylbromide over the ring chloride provides a new procedure for the functionalization of 5-carboxypyrimidines.