摘要:

AbstractIn search of new histamine H3‐receptor ligands sixteen ether derivatives of 3‐(1H‐imidazol‐4‐yl)propanol with benzylic partial structure or related moieties were prepared and investigated as H3‐receptor antagonists. The new compounds belong to a general construction pattern developed by other histamine H3‐receptor antagonists. Structural modifications were introduced in an attempt to optimizein vitroas well asin vivoactivity. Structure‐activity relationships of the new histamine H3‐receptor antagonists are discussed. All ether derivatives showedin vitroactivities in the nanomolar concentration range, but only compounds with bulky lipophilic residues were also active underin vivoconditions. The most active compound within this series was 3‐(1H‐imidazol‐4‐yl)propyl 1‐naphthylmethyl ether (4n) presenting an ED50of 3.2 ± 1.9 mg/kg regarding enhancement of endogenous histamine in brain afterp.o.administration to mice. Furthermore, comparison of the H3‐receptor activities measured on synaptosomes of rat cerebral cortex and on guinea pig ileum gave a good correlation indicating homogeneity of central and peripheral H3‐receptor test models. The most interesting compounds were also evaluated in functionalin vitroassays with regard to their activities at histamine H1‐, H2‐, and muscarinic M3‐receptors. The tested compounds showed very weak activities at these receptor subtypes demon

ISSN:0365-6233    

DOI:10.1002/ardp.19963290802

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

摘要:

Abstract3‐(1‐Acylaminooctadecyl)indole‐2‐carboxylic acids and 3‐(1‐acylaminooctadecyl)‐1‐methylindole‐2‐carboxylic acids were designed and synthesized as inhibitors of cytosolic phospholipase A2. Enzyme inhibition was assayed by evaluation of calcium ionophore A23187‐induced arachidonic acid release from bovine platelets. While compounds with 1‐octadecanoylaminooctadecyl groups in position 3 of the indole were inactive inhibition data for 3‐[1‐(3‐phenylpropionylamino)octadecyl]indole‐2‐carboxylic acids could not be evaluated because of lysis of the platelets. However 3‐(octadecanoylaminomethyl)indole‐2‐carboxylic acid derivatives and 1‐methyl‐3‐octadecanoylindole‐2‐carboxylic acid proved to be inhibitors of cytosolic phospholipase A2. The most active inhi

ISSN:0365-6233    

DOI:10.1002/ardp.19963290803

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

摘要:

AbstractThe synthesis and the anticonvulsant activity of a number of GABA and valproic acid derivatives are reported. The lipophilicity of these compounds and their inhibitory effect on lipid peroxidation were also investigated, in an effort to correlate the anticonvulsant activity with lipophilicity and inhibitory effect on lipid peroxidation. The synthesized compounds exhibited anticonvulsant effects which were stronger for the more lipophilic derivatives. One of the active anticonvulsants showed appreciable antioxidant properties. Finally, a good correlation was found between the experimentally derived (RM) and calculated (σ and logPSK) lipophilicity for this series of compounds

ISSN:0365-6233    

DOI:10.1002/ardp.19963290804

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

摘要:

AbstractAlbumin bindingfor the enantiomers of four closely relatedN‐methyl‐5‐phenyl‐5‐alkyl‐barbiturates1–4was investigated for three different mammalian species by means of equilibrium dialysis. Lipid solubility (n‐heptane/phosphate buffer distribution coefficient) increased stepwise by a factor of 56 from1to4.Bovine serum albumin:The (S)‐(+)‐enantiomers of1–4were bound in a higher percentage than the (R)‐(−)‐enantiomers; lengthening of the aliphatic side‐chain increased the binding extent in both enantiomeric groups.Human serum albumin:Binding of (S)‐(+)‐1and (S)‐(+)‐4was higher than that of the (R)‐(−)‐enantiomers; with (S)‐(+)‐2and (S)‐(+)‐3it was much lower than that of the corresponding (R)‐(−)‐enantiomers. Lengthening of the aliphatic side chain increased the binding extent of the (S)‐(+)‐ as well as of the (R)‐(−)‐enantiomers, but with two exceptions: 1. The (S)‐(+)‐1binding exceeded that of the (S)‐(+)‐2by a factor of nearly two 2. The binding extent of (R)‐(−)‐4was not further increased in comparison to (R)‐(−)‐3.Rat serum albumin:(S)‐(+)‐1and (S)‐(+)‐2were bound in a lower percentage than the (R)‐(−)‐enantiomers, both3‐enantiomers showing an equal binding extent; (S)‐(+)‐4was bound to a slightly greater extent than the (R)‐(−)‐4.In the group of the (S)‐(+)‐enantiomers, the binding extent increased from1to4, whereas in that of the (R)‐(−)‐enantiomers only between1and4.Structural differences between the serum albumins of three mammalian species possibly cause the enantioselective binding pattern found for the enantiomers of1–4, and are r

ISSN:0365-6233    

DOI:10.1002/ardp.19963290805

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

摘要:

AbstractStarting from conveniently accessible ethyl 5‐aroyl‐4‐pyridazine‐carboxylates6representatives of the novel tricyclic systems2(with X = O and X = NH) were synthesised and screened as potential non‐nucleoside HIV‐1 reverse transcriptase

ISSN:0365-6233    

DOI:10.1002/ardp.19963290806

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

摘要:

AbstractA group of racemic alkyl 1,4‐dihydro‐2,6‐dimethyl‐4‐(3‐ or 4‐pyridinyl)‐5‐[2‐(4,5‐dihydro‐4,4‐dimethyloxazolin‐2‐yl)]‐3‐pyridinecarboxylates11a—ewere prepared by using the Hantzsch reaction involving condensation of the Knoevenagel adducts9a—ewith 1‐[2‐(4,5‐dihydro‐4,4‐dimethyloxazolin‐2‐yl)]‐1‐propen‐2‐amine (10). In contrast, the 4‐(2‐pyridinyl) analogue11fwas prepared by thionyl chloride mediated cyclization of the 5‐{N‐(1,1‐dimethyl‐2‐hydroxyethyl)aminocarbonyl} moiety of16to the 5‐[2‐(4,5‐dihydro‐4,4‐dimethyloxazolin‐2‐yl)] ring system (11f).In vitrocalcium channel antagonist activity was determined by using the guinea pig ileum longitudinal smooth muscle (GPILSM) assay. Compared to the reference drug nifedipine (IC50= 1.43 × 10−8M), the title compounds11exhibited weak calcium channel antagonist activity (10−5to 10−6M range). A comparison of compounds11having a C‐4 3‐pyridinyl substituent showed that with respect to the alkyl ester R2‐subsituent, the relative potency order wasi‐Bu (11c) ≥i‐Pr (11e)>Me (11a). The point of attachment of the C‐4 pyridinyl substituent in the isopropyl ester isomeric series of compounds was a determinant of activity where the potency profile was 4‐py (11d) ≥ 3‐py (11e)>2‐py (11f). Although less effective, the 4,5‐dihydro‐4,4‐dimethyloxazolin‐2‐yl moiety acts as a bioisostere of the alkyl ester substituent present in classical 1,4‐dihydropyridine calcium channel antagonists. The 4,5‐dihydro‐4,4‐dimethyl‐oxaxolin‐2‐yl ring system is not an effective bioisostere of the 3‐nitro group present in 1,4‐dihydropyridine calcium channel agonists since isopropyl 1,4‐dihydro‐2,6‐dimethyl‐4‐(2‐pyridinyl)‐5‐[2‐(4,5‐dihydro‐4,4‐dimethyloxazolin‐2‐yl)]‐3‐pyridinecarboxylate (11f) produced a

ISSN:0365-6233    

DOI:10.1002/ardp.19963290807

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

摘要:

AbstractFollowing up the finding that the non‐imidazole drug clozapine shows a considerable histamine H3receptor antagonistic activity[1,2], a series of analogues and metabolites (clozapine‐N‐oxide, andN‐desmethylclozapine) were tested for their affinity towards the H3receptor using the radiolabelled H3antagonist [125I]‐iodophenpropit.Qualitative structure affinity relationships are derived for the tested compounds. In the clozapine molecule four structurally different moieties may be considered. In comparison with the affinity for the H3receptor shown by clozapine, the following main conclusions can be drawn: The 4‐piperazinyl region does not allow substituents longer than a CH3or electronegative atoms such as an O (as in clozapine‐N‐oxide); the lack of the CH3group (as inN‐desmethylclozapine) also reduces the affinity for H3receptors. Substitutions at the 5‐diazepine position do not drastically alter the affinity for the H3receptor, although a basic nitrogen is favoured over CH2, O, or S. The 8 position in ring I is an important modulatory site for H3affinity; electronegative substituents such as chloro and fluoro in this aromatic ring increase the affinity. When these substituents are, however, present at position X2in the ring, they disable binding to the H3receptor.The two major clozapine metabolites (clozapine‐N‐oxide, andN‐desmethylclozapine) will not be responsible for a possible contribution of the H3receptor antagonism to the clin

ISSN:0365-6233    

DOI:10.1002/ardp.19963290808

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

摘要:

AbstractAspirin (O‐acetylsalicylic acid) has been used to synthesize prodrugs of 3′‐azido‐3′‐deoxythymidine (AZT) and 3′‐deoxy‐3′‐fluorothymidine (FLT). The mixed anhydride between aspirin and trifluoroacetic acid was synthesized and reacted with AZT and FLT to give the blocked nucleosides attached through the 5′‐Oposition to the 2‐position of 2‐methyl‐4H‐1,3‐benzodioxin‐4‐one. The prodrugs showed the same activities against HIV‐1 in MT‐4 cells as the original drugs. Hydrolysis of the synthesized prodrugs in the growth medium, used for anti‐HIV investigations, resulted in formation of 5‐Oacetylated drugs which were

ISSN:0365-6233    

DOI:10.1002/ardp.19963290809

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

摘要:

AbstractA series ofN‐(2‐hydroxyethyl)‐1,2‐benzisothiazol‐3(2H)‐one and ‐thione carbamic esters have been synthesised and tested againstMycobacterium aviumstrains. The MIC values determined by the radiometric broth dilution method were between 2 and 8 μg/mL for the benzisothiazolthione derivatives and between 16 and 32 μg/mL or higher for the corresponding benzisothiazol

ISSN:0365-6233    

DOI:10.1002/ardp.19963290810

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

摘要:

AbstractA series of 4‐(alkylidene/arylidene)amino‐5‐(2‐furanyl)‐2,4‐dihydro‐3H‐1,2,4‐triazole‐3‐thiones (2) and 6‐aryl‐3‐(2‐furanyl)‐7H‐1,2,4‐triazolo[3,4‐b][1,3,4]thiadiazines (3) were synthesized. The configuration of2gwas assigned on the basis of1H‐NMR data. Of the new derivatives tested, only2b, 2g, and4fwere found to be active againstStaphylococcus aureusand/orStaphylococcus epidermidis(MIC 125–1.95 μg/ml), whereas all exhibited varying degrees

ISSN:0365-6233    

DOI:10.1002/ardp.19963290811

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY