The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy.

RPR132331, a 2-(2-dioxanyl)imidazole, was identified as an inhibitor of tumour necrosis factor (TNF)alpha release from lipopolysaccharide (LPS)-stimulated human monocytes. An intensive programme of work exploring the biology, toxicity and physical chemistry of a novel series of inhibitors, derived from RPR132331, has led to the identification of RPR200765A, a development candidate for the treatment of rheumatoid arthritis (RA). RPR200765A is a potent and selective inhibitor of p38 MAP kinase (IC50 = 50 nM). It inhibits LPS-stimulated TNFalpha release both in vitro, from human monocytes (EC50 = 110 nM), and in vivo in Balb/c mice (ED50 = 6 mg/kg). At oral doses between 10 and 30 mg/kg/day it reduces the incidence and progression in the rat streptococcal cell wall (SCW) arthritis model when administered in either prophylactic or therapeutic dosing regimens. The compound, which is a mesylate salt and exists as a stable monohydrate, shows good oral bioavailabiltiy (F = 50% in the rat) and excellent chemical stability. The data from the SCW disease model suggests that RPR200765A could exhibit a profile of disease modifying activity in rheumatoid arthritis (RA) patients which is not observed with current drug therapies.

An investigation into the use of polymer gel dosimetry in low dose rate brachytherapy.

An investigation has been carried out into the properties of the BANG polymer gel and its use in the dosimetry of low dose rate brachytherapy. It was discovered that the response of the gel was reproducible and linear to 10 Gy. The gel was found to be tissue equivalent with a response independent of energy to within experimental accuracy (standard error of measurement +/- 5%). The slope of the calibration curve was found to increase from 0.28 +/- 0.01 s-1 Gy-1 to 0.50 +/- 0.02 s-1 Gy-1 for an increase in monomer concentration from 6 to 9%. Absorbed dose distributions for a straight applicator containing 36 137Cs sources were measured using the gel and the results compared with measurements made with thermoluminescent dosemeters (TLDs) and calculated values. Good agreement was found for the relative measurements. The root mean square residual percentage errors were 3%, 1% and 4% for the gel and the two groups of TLDs, respectively. There were some significant differences in absolute values of absorbed dose in the gel, possibly owing to the effects of oxygen. Measurements of a complex gynaecological insert were also made and compared with isodose curves from a planning system (Helax TMS), and in areas unaffected by oxygen diffusion the isodose levels from 100 to 50% agreed to within less than 0.5 mm.

Selective type IV phosphodiesterase inhibitors as antiasthmatic agents. The syntheses and biological activities of 3-(cyclopentyloxy)-4-methoxybenzamides and analogues.

The syntheses and biological activities of a number of benzamide derivatives, designed from rolipram, which are selective inhibitors of cyclic AMP-specific phosphodiesterase (PDE IV), are described. The effects of changes to the alkoxy groups, amide linkage, and benzamide N-phenyl ring on the inhibition of the cytosolic PDE IV from pig aorta have been investigated. As a result, some highly potent and selective PDE IV inhibitors have been identified. The most potent compounds have been further evaluated for their inhibitory potencies against PDE IV obtained from and superoxide O2- generation from guinea pig eosinophils in vitro. Selected compounds have also been examined for their activities in inhibiting histamine-induced bronchospasm in anaesthetized guinea pigs. 3-(Cyclopentyloxy)-N-(3,5-dichloro-4-pyridyl)-4-methoxybenzamide (15j) showed exceptional potency in all tests and may have therapeutic potential in the treatment of asthma.

Application of n-pentenyl glycosides in the regio- and stereo-controlled synthesis of alpha-linked N-glycopeptides.

The N-glycopeptides alpha-Glc-(1----Asn and alpha-Glc-(1----6)-beta-Glc- (1----6)-alpha-Glc-(1----Asn have been synthesized efficiently from pent-4-enyl D-glucopyranoside derivatives. The methodology illustrates (a) a novel route for formation of the N-alpha-D-glucosyl-asparagine link, and (b) stereo-controlled construction of the glycan backbone alpha-Glc-(1----6)-beta-Glc-(1----6)-Glc in which the reactivity of each pentenyl glycosyl donor is controlled by an appropriate promoter. This strategy minimizes the number of changes of protecting groups that is required.