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Christopher Hulme

Publications and source records attributed to Christopher Hulme.

8 recordsLinked to original sources
PubMed2006

Solid-phase synthesis and structure-activity relationships of novel biarylethers as melanin-concentrating hormone receptor-1 antagonists.

Melanin-concentrating hormone (MCH) is a cyclic 19 amino acid orexigenic neuropeptide. The action of MCH on feeding is thought to involve the activation of its respective G protein-coupled receptor MCH-R1. Consequently, antagonists that block MCH regulated MCH-R1 activity may provide a viable approach to the treatment of diet-induced obesity. This communication reports the discovery of a novel MCH-R1 receptor antagonist, the biarylether 7, identified through high throughput screening. The solid-phase synthesis and structure-activity relationship of related analogs is described.

Combinatorial Chemistry Techniques↗
PubMed2005

Health outcome measures in the evaluation of total hip arthroplasties--a comparison between the Harris hip score and the Oxford hip score.

There has been an increasing need for the sensitive and reproducible measurement of the outcome after hip surgery. Numerous hip scoring systems, varying in their complexity and disease specificity, have been designed to achieve a measure of outcome-some rely ultimately on the judgement of the surgeon, whereas others rely on the patients' perceptions. The Oxford hip score (OHS) has been found to be easier to administer and achieves a much higher follow-up rate than that of the Harris hip score (HHS). Unfortunately, with the availability of numerous scoring systems and the publication of data in these systems, it has been difficult to compare results. Our aim was to compare the more widely used HHS to the shorter OHS. We followed 200 consecutive primary total hip arthroplasties (196 patients between January 1994 and May 1995) for an average of 5 years. All patients had a preoperative HHS recorded. At the 5-year review, assessment was made using OHS and the HHS. There were 115 hips that had full OHS and HHS available. The mean OHS was 19.1 (range 12-52, SD 9.5), and HHS was 89.4 (range 47-100, SD 13.3) at follow-up. The Spearman correlation showed good negative correlation between the 2 results (Spearman rank -0.712, P < .0001). The HHS vs OHS shows good correlation at 5 years. This is the first study to confirm that correlation persists for the OHS in the medium term. We include a classification of OHS of excellent (<19), good (19-26), fair (27-33), and poor (>33) outcomes which correlate well with the HHS. This study enables the case for the Oxford data with its easier analysis and higher compliance rate to be used more directly to compare studies that use the HHS.

Adult↗
PubMed2004

Is the Charnley evolution working? A five-year outcome study.

Two hundred consecutive primary total hip arthroplasties (196 patients) carried out between January 1994 and May 1995 using the Elite Plus cemented femoral components (DePuy International, Leeds, UK) were enrolled in a prospective study. Fifteen patients were lost to follow-up. The patients were evaluated clinically using the Harris Hip Score (HHS) and radiographically. The mean HHS was raised from 39.3 preoperatively to 89.6 at 5 years. Radiologically the mean femoral subsidence was 1.40 mm at 5 years. The mean annual rate of re-operation was 0.2%. There were no revisions for aseptic loosening. In the present series, the Elite Plus hip arthroplasty has produced clinical and radiological results, which are comparable with the Charnley hip at five years.

Adult↗
PubMed2003

One-pot microwave assisted preparation of pyrazoloquinazolinone libraries.

The novel solution-phase synthesis of an array of biologically relevant pyrazoloquinazolinones in a simple microwave driven one pot procedure is revelaed. Transformations are carried out in good to excellent yield by condensation of alpha-cyano-ketones and 2-hydrazino-benzoic acids. Subsequent microwave irradiation affords pyrazoloquinazolinones with six points of potential diversification. The protocol described represents a very attractive solution phase procedure for the rapid generation of arrays of such functionalized cores, further demonstrating the growing importance of economic and enabling complexity generating chemistries in the lead discovery arena.

Chemistry, Organic↗
PubMed2003

"Multi-component reactions : emerging chemistry in drug discovery" 'from xylocain to crixivan'.

With the recent emergence of combinatorial chemistry and high-speed parallel synthesis for drug discovery applications, the multi-component reaction (MCR) has seen a resurgence of interest. Easily automated one-pot reactions, such as the Ugi and Passerini reactions, are powerful tools for producing diverse arrays of compounds, often in one step and high yield. Despite this synthetic potential, the Ugi reaction is limited by producing products that are flexible and peptide-like, often being classified as 'non drug-like'. This review details developments of new, highly atom-economic MCR derived chemical methods, which enable the fast and efficient production of chemical libraries comprised of a variety of biologically relevant templates. Representative examples will also be given demonstrating the successful impact of MCR combinatorial methods at different stages of the lead discovery, lead optimization and pre-clinical process development arenas. This will include applications spanning biological tools, natural products and natural product-like diversity, traditional small molecule and 'biotech' therapeutics respectively. In particular, this review will focus on applications of isocyanide based MCR (IMCR) reactions.

Animals↗
PubMed2003

Rapid assembly of molecular diversity via exploitation of isocyanide-based multi-component reactions.

Molecular diversity is the variability of physical properties between molecules, viewed in terms of molecular shape, polarity/charge, lipophilicity, polarizability and flexibility. Due to their widespread medicinal properties, natural products were one of the original sources of molecular diversity; however, new developments in the search for novel pharmacological agents over the last decade have focused on the preparation of chemical libraries as the source of new leads for drug discovery. A plethora of personal synthesizers and new automation technologies have emerged to help fuel the lead discovery engines of drug discovery organizations. Multistep solid-phase syntheses of diverse libraries in excess of 10,000 products can now be prepared via split-and-mix techniques. Simultaneously, a multitude of more efficient, diversity- or target-oriented solution-phase chemical methodologies have appeared in the chemical literature, enabling the relatively facile construction of successful lead generation libraries with low full-time equivalent input and little capital expenditure. Isocyanide-related multi-component reactions hold a pre-eminent position in this regard, and are finding increasing applications in the discovery process of new drugs and agrochemicals. This review is the authors' personal assessment of advances in the field over the last two years (2002 to 2003), with little emphasis placed on highly mechanistic details.

Combinatorial Chemistry Techniques↗
PubMed2002

Knowledge-based approaches in the design and selection of compound libraries for drug discovery.

In the past decade, the pharmaceutical industry has realized the increasing significance of impacting the early phase hit-to-lead development in the drug discovery process. In particular, knowledge-based approaches emerged and evolved to address a multitude of issues such as absorption, distribution, metabolism and excretion (ADME), potency, toxicity and overall drugability. Each of these approaches seeks to bring together all relevant pieces of information and create a knowledge-oriented process to deploy such information in drug discovery. This review focuses on work relating to drugability, which aims at obtaining hits (or leads) that have enhanced likelihoods of leading to successful clinical candidates by medicinal chemistry efforts. The period covered in this review is from 1997 (since the publication of Lipinski's rule of 5) to March 2002.

Animals↗