Publications by authors named "Dieter W Hamprecht"

5 Publications

  • Page 1 of 1

Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists.

Bioorg Med Chem Lett 2005 Nov;15(21):4867-71

Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

Starting from the potent and selective but poorly brain penetrant 5-HT6 receptor antagonist SB-271046, a successful strategy for improving brain penetration was adopted involving conformational constraint with concomitant reduction in hydrogen bond count. This provided a series of bicyclic heteroarylpiperazines with high 5-HT6 receptor affinity. 5-Chloroindole 699929 combined high 5-HT6 receptor affinity with excellent brain penetration and also had good oral bioavailability in both rat and dog.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2005.06.107DOI Listing
November 2005

Definition of the heterocyclic pharmacophore of bacterial methionyl tRNA synthetase inhibitors: potent antibacterially active non-quinolone analogues.

Bioorg Med Chem Lett 2004 Aug;14(15):3937-41

GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

Potent inhibitors of bacterial methionyl tRNA synthetase (MRS) have previously been reported. Through SAR of the quinolone moiety, the right hand side pharmacophore for MRS inhibition has now been defined as an NH-C-NH functionality in the context of a bicyclic heteroaromatic system. Potent antibacterial fused-pyrimidone and fused-imidazole analogues have been obtained and enantioselective activity demonstrated. Compound 46 demonstrated very good antibacterial activity against panels of antibiotic-resistant staphylococci and enterococci.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2004.05.070DOI Listing
August 2004

Synthesis of 2-substituted benzofurans and indoles using functionalized titanium benzylidene reagents on solid phase.

J Org Chem 2003 Jan;68(2):387-401

Department of Chemistry, University of Glasgow, UK.

Titanium(IV) benzylidenes bearing a masked oxygen or nitrogen nucleophile in the ortho position were generated from thioacetals, using low-valent titanocene complex, Cp2Ti[P(OEt)3]2. Methylene acetal, alkyl ether, silyl ether, fluoro, tertiary amino, and N-alkyl, N-benzyl, N-prenyl, and N-silyl tert-butyl carbamate groups were tolerated in the titanium alkylidene reagents (Schrock carbenes). Aryl-chlorine bonds were stable to the titanium benzylidene functionality, but there was poor chemoselectivity for the reduction of the thioacetal in the presence of an aryl chloride. The titanium benzylidenes converted Merrifield and Wang resin-bound esters into enol ethers. The oxygen nucleophile was masked as a TMS ether, and when the resin-bound enol ethers bearing this ortho substituent were treated with 1% TFA in dichloromethane, benzofurans were released from resin in high yields. The chameleon catch strategy ensured excellent purity. In a similar way, N-alkylated and N-silylated tert-butyl carbamates were used for the synthesis of N-alkyl and N-Boc indoles, respectively. These traceless solid-phase syntheses of heterocycles are believed to involve postcleavage modification rather than cyclative termination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo026384oDOI Listing
January 2003

The antimicrobial natural product chuangxinmycin and some synthetic analogues are potent and selective inhibitors of bacterial tryptophanyl tRNA synthetase.

Bioorg Med Chem Lett 2002 Nov;12(21):3171-4

GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

The antimicrobial natural product chuangxinmycin has been found to be a potent and selective inhibitor of bacterial tryptophanyl tRNA synthetase (WRS). A number of analogues have been synthesised. The interaction with WRS appears to be highly constrained, as only sterically smaller analogues afforded significant inhibition. The only analogue to show inhibition comparable to chuangxinmycin also had antibacterial activity. WRS inhibition may contribute to the antibacterial action of chuangxinmycin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0960-894x(02)00604-2DOI Listing
November 2002

Novel functionalized titanium(IV) benzylidenes for the traceless solid-phase synthesis of indoles.

Org Lett 2002 Jan;4(1):75-8

Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK.

[reaction: see text] Titanium(IV) benzylidenes bearing a masked nitrogen nucleophile in the ortho position converted Merrifield resin-bound esters into enol ethers. An unusual nitrogen protecting group, N-silylated tert-butyl carbamate, was employed. One percent TFA released N-Boc indoles in high yield and purity. N-Methyl indoles were also prepared. Cyclative termination was not required to release the chameleon catch. The first example of a carbonyl group within a titanium alkylidene reagent is reported.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ol016924oDOI Listing
January 2002