Biomedical subjects

Janet Cheetham

Publications and source records attributed to Janet Cheetham.

5 recordsLinked to original sources

PubMed2005

Supercritical fluid chromatography tandem-column method development in pharmaceutical sciences for a mixture of four stereoisomers.

A tandem-column method using Chiralpak AD-H and Chiralcel OD-H columns was achieved for baseline separation of a mixture of chiral pharmaceutical compounds (i.e., four stereoisomers) via supercritical fluid chromatography (SFC) with a mobile phase consisting of 90% liquid carbon dioxide and 10% ethanol:isopropanol (50:50 v/v). On the contrary, this mixture (mixture A) could not be baseline separated by SFC conditions explored with individual Chiralpak AD-H and Chiralcel OD-H columns. The effects of various mobile phases on elution order, capacity factor, selectivity, and resolution were determined with mixture A on the individual aforementioned columns to develop the tandem-column method.

Chromatography, Liquid↗

PubMed2004

(4-Piperidinylphenyl)aminoethyl amides as a novel class of non-covalent cathepsin K inhibitors.

A series of (4-piperidinylphenyl)aminoethyl amides based on dipeptide anilines were synthesized and tested against cathepsin K, cathepsin L and cathepsin B. These new non-covalent inhibitors exhibited single-digit nM inhibition of the cysteine proteases. Compounds 3 and 7 demonstrated potency in both mouse and human osteoclast resorption assays.

Amides↗

PubMed2003

Design of a new peptidomimetic agonist for the melanocortin receptors based on the solution structure of the peptide ligand, Ac-Nle-cyclo[Asp-Pro-DPhe-Arg-Trp-Lys]-NH(2).

The solution structure of a potent melanocortin receptor agonist, Ac-Nle-cyclo[Asp-Pro-DPhe-Arg-Trp-Lys]-NH(2) (1) was calculated using distance restraints determined from 1H NMR spectroscopy. Eight of the lowest energy conformations from this study were used to identify non-peptide cores that mimic the spatial arrangement of the critical tripeptide region, DPhe-Arg-Trp, found in 1. From these studies, compound 2a, containing the cis-cyclohexyl core, was identified as a functional agonist of the melanocortin-4 receptor (MC4R) with an IC(50) and EC(50) below 10 nM. Compound 2a also showed 36- and 7-fold selectivity over MC3R and MC1R, respectively, in the binding assays. Subtle changes in cyclohexane stereochemistry and removal of functional groups led to analogues with lower affinity for the MC receptors.

Drug Design↗

PubMed2003

Structure-activity relationship of (1-aryl-2-piperazinylethyl)piperazines: antagonists for the AGRP/melanocortin receptor binding.

Agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin action.(1) In the hypothalamus, melanocortin peptide agonists act as satiety-inducing factors that mediate their action through the melanocortin-4 receptor (MC4R) whereas AGRP is an opposing orexigenic agent. Novel inhibitors of the AGRP/MC4 binding based on (piperazinylethyl)piperazines were prepared, and their structure-activity relationship was established.

Agouti-Related Protein↗

PubMed2003

Solubility prediction by recursive partitioning.

PURPOSE: To build and test a computational model for predicting small molecule solubility, to improve the cost-effectiveness of the selection of vendor compounds suitable for nuclear magnetic resonance (NMR) screening. METHODS: A simple recursive partitioning decision tree-based classification model was generated utilizing "off-the-shelf" commercial software from Accelrys Inc., with a training set of 1992 compounds based on a series of calculated topologic and physical properties. The predictive ability of the decision tree was then assessed by employing it to classify a test set of 2851 vendor compounds, and the classification was subsequently used to guide the purchase of 686 compounds for the purpose of NMR screening. RESULTS: When the decision tree was used to guide purchasing, the percentage of "acceptable" compounds suitable for NMR screening doubled compared with the use of a simple cLogP cutoff, improving the successful selection rate from 25% to 50%. CONCLUSIONS: A simple recursive partitioning decision tree may successfully be used to improve cost-effectiveness by reducing the wastage associated with the unnecessary purchase of vendor compounds unsuitable for NMR screening because of insolubility.

Computer Simulation↗