Dipeptidyl nitriles as human dipeptidyl peptidase I inhibitors.

Using a dipeptide nitrile scaffold we have identified a potent and selective inhibitor of human dipeptidyl peptidase I.

Novel semicarbazide-derived inhibitors of human dipeptidyl peptidase I (hDPPI).

Human dipeptidyl peptidase I (hDPPI, cathepsin C, EC 3.4.14.

Isoxazole-3-hydroxamic acid derivatives as peptide deformylase inhibitors and potential antibacterial agents.

A series of isoxazole-3-hydroxamic acid derivatives has been identified as a new class of small, nonpeptidic inhibitors of peptide deformylase (PDF). The synthesis, enzyme inhibition and preliminary investigation of the binding mode of this potential antibacterial compounds are reported.

Efficient generation, storage, and manipulation of fully flexible pharmacophore multiplets and their use in 3-D similarity searching.

Pharmacophore triplets and quartets have been used by many groups in recent years, primarily as a tool for molecular diversity analysis. In most cases, slow processing speeds and the very large size of the bitsets generated have forced researchers to compromise in terms of how such multiplets were stored, manipulated, and compared, e.g.

Virtual screening for submicromolar leads of tRNA-guanine transglycosylase based on a new unexpected binding mode detected by crystal structure analysis.

Eubacterial tRNA-guanine transglycosylase (TGT) is involved in the hypermodification of cognate tRNAs, leading to the exchange of G34 by preQ1 at the wobble position in the anticodon loop. Mutation of the tgt gene in Shigella flexneri results in a significant loss of pathogenicity of the bacterium due to inefficient translation of a virulence protein mRNA. Herein, we describe the discovery of a ligand with an unexpected binding mode.

Scaffold hopping and optimization towards libraries of glycogen synthase kinase-3 inhibitors.

Using a virtual screening strategy based on a methodology derived from the CATS molecular descriptor, a novel compound class with inhibitory activity against the GSK-3 enzyme was identified through scaffold hopping. These compounds were readily synthesized, either by solid-phase or solution-phase chemistry. Compounds with inhibitory activity below 1 microM were identified.

Synthesis and pharmacological evaluation of novel cis-3,4-diaryl-hydroxychromanes as high affinity partial agonists for the estrogen receptor.

The syntheses and in vitro pharmacological evaluation of a number of cis-3,4-diaryl-hydroxy-chromanes are reported, along with the results of a thorough in vivo profiling of the tissue-selective estrogen partial-agonist NNC 45-0781 [3, (-)-(3S,4R)-7-hydroxy-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane]. These studies showed that NNC 45-0781 is a very promising candidate for the prevention of post-menopausal osteoporosis, and the treatment of other health issues related to the loss of endogenous estrogen production.

Synthesis and biological evaluation of novel thio-substituted chromanes as high-affinity partial agonists for the estrogen receptor.

Synthesis of (+/-)-cis-7-hydroxy-3-phenyl-4-(4-(2-piperidinoethanethio)phenyl)chromane (13) and (+/-)-cis-7-hydroxy-3-phenyl-4-(4-(2-pyrrolidinoethanethio)phenyl)chromane (15) is presented. These compounds are representatives of a novel class of compounds with high in vitro binding affinity for the estrogen receptor (IC(50)=7-10 nM), and very low in vitro uterotrophic activity (max stim.=5-17% rel to moxestrol; EC(50)=0.