Pete Dunten

Discovery of piperidin-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-benzyl derivatives with broad potency against resistant mutant viruses.

An analysis of the binding motifs of known HIV-1 non-nucleoside reverse transcriptase inhibitors has led to discovery of novel piperidine-linked aminopyrimidine derivatives with broad activity against wild-type as well as drug-resistant mutant viruses. Notably, the series retains potency against the K103N/Y181C and Y188L mutants, among others. Thus, the N-benzyl compound 5k has a particularly attractive profile. Synthesis and SAR are presented and discussed, as well as crystal structures relating to the binding motifs.

X-ray structure of a novel matrix metalloproteinase inhibitor complexed to stromelysin.

A new class of matrix metalloproteinase (MMP) inhibitors has been identified by screening a collection of compounds against stromelysin. The inhibitors, 2,4,6‐pyrimidine triones, have proven to be potent inhibitors of gelatinases A and B. An X‐ray crystal structure of one representative compound bound to the catalytic domain of stromelysin shows that the compounds bind at the active site and ligand the active‐site zinc. The pyrimidine triones mimic substrates in forming hydrogen bonds to key residues in the active site, and provide opportunities for placing appropriately chosen groups into the S1′ specificity pocket of MMPs. A number of compounds have been synthesized and assayed against stromelysin, and the variations in potency are explained in terms of the binding mode revealed in the X‐ray crystal structure.

Novel 5,5-disubstitutedpyrimidine-2,4,6-triones as selective MMP inhibitors

The 5,5-disubstitutedpyrimidine-2,4,6-triones represent a new class of MMP inhibitors showing selectivity for the gelatinases A and B, collagenase-3, and human neutrophil collagenase. The SAR presented here is in good agreement with an X-ray structure of compound 5 bound to the catalytic domain of stromelysin-1. While of the barbiturate structural class, compound 5 did not show any toxic or sedative effects.

Discovery and optimization of pyridazinone non-nucleoside inhibitors of HIV-1 reverse transcriptase.

A series of benzyl pyridazinones were evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Several members of this series showed good activity against the wild-type virus and NNRTI-resistant viruses. The binding of inhibitor 5a to HIV-RT was analyzed by surface plasmon resonance spectroscopy. Pharmacokinetic studies of 5a in rat and dog demonstrated that this compound has good oral bioavailability in animal species. The crystal structure of a complex between HIV-RT and inhibitor 4c is also described.

Discovery of potent and bioavailable GSK-3β inhibitors

Here we report on the discovery of a series of maleimides which have high potency and good selectivity for GSK-3beta. The incorporation of polar groups afforded compounds with good bioavailability. The most potent compound 34 has an IC(50) of 0.6nM for GSK-3beta, over 100-fold selectivity against a panel of other kinases, and shows efficacy in rat osteoporosis models. The X-ray structure of GSK-3beta protein with 34 bound revealed the binding mode of the template and provided insights for future optimization opportunities.

Modified 3-alkyl-1,8-dibenzylxanthines as GTP-competitive inhibitors of phosphoenolpyruvate carboxykinase

The first non-substrate like inhibitors of human cytosolic phosphoenolpyruvate carboxykinase (PEPCK) competitive with GTP are reported. An effort to discover orally active compounds that improve glucose homeostasis in Type 2 diabetics by reversibly inhibiting PEPCK led to the discovery of 1-allyl-3-butyl-8-methylxanthine (5). We now report modifications at N-1 and C-8 that improved the in vitro activity of the initial xanthine HTS hit by 100-fold and a developing SAR for this class of inhibitor.

X-ray structures of two xanthine inhibitors bound to PEPCK and N-3 modifications of substituted 1,8-dibenzylxanthines.

The analysis of the X-ray structures of two xanthine inhibitors bound to PEPCK and a comparison to the X-ray structure of GTP bound to PEPCK are reported. The SAR at N-1, N-7 and developing SAR at C-8 are consistent with information gained from the X-ray structures of compounds 1 and 2 bound to PEPCK. Representative N-3 modifications of compound 2 that led to the discovery of 3-cyclopropylmethyl and its carboxy analogue as optimal N-3 groups are presented.