Discovery of 4-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)-oxazolidin-2-one (4991W93), a 5HT(1B/1D) receptor partial agonist and a potent inhibitor of electrically induced plasma extravasation.

Utilizing a pharmacophoric model of binding of 3-(2-aminoethyl)indoles to 5HT(1B/1D) receptors, we identified the 3-aminocyclobutyl group as a potential ethylamine isostere. A novel multidimensional chemometric approach was used to predict the intrinsic activity (degree of agonism) at the receptor. A qualitative model for pharmacokinetic properties was then used to guide the synthesis toward molecules likely to have oral bioavailability in humans. A novel synthetic route to 3-(3-dimethylaminocyclobutyl)indoles was developed. Analogues showed generally lower intrinsic activity at 5HT(1B/1D) receptors than their ethylamine counterparts. 4-[3-(trans-3-Dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)-oxazolidin-2-one (4991W93, 1) was identified as a partial agonist against 5HT(1B/1D) receptors, with low intrinsic activity. This molecule also has significant activity against 5HT(1F) receptors but is selective over other 5HT receptors. In addition this compound was found to be an exceptionally potent inhibitor of electrically induced plasma extravasation. Compound 1 may have utility in the treatment and prophylaxis of migraine.

Experience of changing between signal and Bactec 9240 blood culture systems in a children's hospital.

AIM: To compare experience of positive blood cultures in successive years before and after changing from Signal (Unipath) to Bactec 9240 (Becton Dickinson) blood culture systems. METHODS: Analysis of data collected prospectively on 7967 Signal and 7062 Bactec blood culture sets. RESULTS: Significant growths occurred in 5.7% of Signal and 8.9% of Bactec cultures; 33.0% more significant isolates and 24.0% more episodes of bacteraemia were detected in the second year, following introduction of the Bactec system. Inpatient hospital activity increased by 8.2% between the first and second years, although the numbers of blood cultures received actually fell by 11.4%. There were striking increases in numbers of isolates of coagulase negative staphylococci (47.7%) and Enterobacteriaceae (56.8%) from Bactec cultures. Two anaerobic bacteraemias were detected in Signal blood cultures, whereas none was detected by the Bactec system, despite 12.1% of sets including an anaerobic bottle. Of significant positive cultures, 90.2% were detected within one day with the Bactec 9240, compared with only 50.0% of Signal cultures; 20.7% of significant positive Signal blood cultures were detected only on terminal subculture. Microorganisms that were not significant were isolated from 5.1% Signal and 3.8% Bactec cultures. CONCLUSIONS: Compared with the Signal system, the Bactec 9240 offers markedly more rapid and sensitive detection of bacteraemia, together with a lower rate of non-significant isolates. However, using a single PEDS PLUS/F bottle the few episodes of anaerobic bacteraemia that occur in children are likely to be missed.

Development of a novel series of trialkoxyaryl derivatives as specific and competitive antagonists of platelet activating factor.

The synthesis and structure-activity relationship (SAR) analysis of a novel series of trialkoxyaryl derivatives, as specific and competitive inhibitors of platelet activating factor (PAF), are described. Molecular modeling comparisons of PAF with the known antagonists Ginkgolide B and L-652731 led to the selection of N-[2-[(3,4,5-trimethoxybenzoyl)oxy]ethyl]-N,N,N-trimethylammonium iodide (1) from the Wellcome registry of compounds and to the synthesis of the lead compound N-[2-[[4-(hexyloxy)-3,5-dimethoxybenzoyl]oxy]ethyl]-N,N,N- trimethylammonium iodide (3, pKb 5.43). Further SAR considerations directed the design to 2-(hexyloxy)-1,3-dimethoxy-5-[4-(4-methylthiazol-5-yl)butyl] benzene (38) (pKb 7.14), a novel, specific, and competitive inhibitor of the PAF receptor in rabbit-washed platelets.

Synthesis and inhibitory activity on platelet aggregation of 13'-aza and other omega-chain modified BW245C analogues.

BW245C analogues which have 15'-keto, -oximino, -sulphinyl, -sulphonyl, -methyl, -1-adamantyl, 14'-hydroxy, 16'-hydroxy, 13'-14'-NH=CH, -NH-CH2, or -NH-CO groups have been synthesized and evaluated for their activity in inhibiting platelet aggregation and for their cardiovascular actions: the 13'-aza analogues 13 and 14 are more potent inhibitors of human platelet aggregation than BW245C (0.3, 0.6 and 0.2 x PGI2, respectively) and these inhibitory activities on platelet aggregation increase on incubation in vitro. The prostaglandin mimetic properties of 13 (BW68C) and 14 (BW361C) were studied in more detail and their platelet inhibitory and vasodilatory effects found to be of longer duration than those of BW245C. All other modifications to the omega-chain of BW245C led to less potent or inactive compounds.