摘要:

Abstract4′,17‐Dioxo‐5′H‐estra‐1(10),4‐dieno[3,2‐b]furan (3) has been prepared by several routes starting from 2‐bromoacetylestrone (2). Performance of the reaction with thiourea at elevated temperature provided compound3in good yield. When other reagents such as thiosemicarbazide, morpholine, sodium hydroxide or sodium hydride were treated with2‐bromoacetylestrone at room temperature, the furano derivative3was also obtained as the sole product. This new type of structural modification provided an estrogen nucleus deprived of the 3‐hydroxyl function which was previously thought to be an essential requisite for binding to the estrogen receptor (ER). When evaluatedin vitrofor binding to the ER andin vivofor uterotrophic and antifertility activities, the furano derivative3was capable of inhibiting[3H]E2binding by 16% while still eliciting high uterotrophic (99%) and postcoital antimplantation (100%) activities

ISSN:0365-6233    

DOI:10.1002/ardp.19963290202

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

摘要:

AbstractSynthesis of several 5‐substituted (2′S)‐2′‐deoxy‐2′‐C‐methylcytidines (8) and ‐uridines (6, 11) has been accomplished using radical deoxygenation of the 2′‐tert‐alcohols via their methyl oxalyl esters as a key reaction. Anti‐herpes simplex virus type‐1 and ‐2, and anti‐varicella‐zoster virus activities of the newly synthesized nucleosides were evaluated. Among them, the 5‐iodouracil derivative6eshowed the most potent activity against herpes simplex virus type‐1, with an EC50of 0.14 μg/mL without showing cytotoxicity up to 100 μg/mL, but had a weak activity against herpes simplex virus type‐2 and no activity against varicella‐zoster virus up to 50 μg/mLin vitro.Although the 5‐fluorocytosine derivative8bhad a potent anti‐herpes simplex virus type‐1 activity (EC50= 0.22 μg/mL), it was rather cytotoxic

ISSN:0365-6233    

DOI:10.1002/ardp.19963290203

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

摘要:

AbstractBiphenyl nitriles5a—c, terphenyl dinitriles11a—d, and naphthalene‐bis(benzonitrile)11ewere prepared by palladium‐catalyzed cross coupling reactions and subsequently converted to biphenyl amidines8a—cand bis(benzamidines)4a—e.Among the biphenyl amidines8only themeta‐derivative8binhibits factor Xa and trypsin (Ki= 10 μM). The terphenyl bisamidine4cdoes not inhibit factor Xa, trypsin, thrombin, and plasmin, while4aand4dare almost equipotent inhibitors of theses enzymes (Ki1–6 μM), and4band4eare selective for trypsin (Ki= 0.2 and 0.3 μM; butKi>1 μM for factor Xa, thrombin, and plasmin). X‐ray analysis of crystals of4bcomplexed with bovine trypsin revealed a unique binding mode: one benzamidino group binds in the S1 site to the side chain carboxylate of Arg189. The central phenyl group is twisted away from the S2/S3 sites and the second amidino group contacts

ISSN:0365-6233    

DOI:10.1002/ardp.19963290204

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

摘要:

AbstractFive 1‐oximino‐1‐nitro compounds (nitrolic acids) were prepared and tested for antithrombotic and blood pressure lowering activities. 1‐Nitro‐ethanone 1‐oxime (1, ethylnitrolic acid) 2 h after oral administration to rats inhibited thrombus formation by a laser beam in mesenteric arterioles of rats by 69% and by 46% in venules (60 mg/kg). The blood pressure of SHR rats even at this high dose only was decreased by 10% suggesting that antithrombotic and blood pressure effects can be dissociated. Thein vitrodecomposition of1at 37 °C nearly exclusively gave N2O and acetic acid indicating that HNO primarily had

ISSN:0365-6233    

DOI:10.1002/ardp.19963290205

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

摘要:

AbstractThe classical histamine H1‐receptor antagonists diphenhydramine (3a) and cyproheptadine (9) and their derivatives (3b—d, 10) were connected with a 2‐guanidinothiazole containing structure (28) derived from the H2‐receptor antagonist tiotidine in order to obtain combined H1‐/H2‐receptor antagonists. The two moieties were not directly linked together, but were separated by a polymethylene spacer and a polar group (nitroethenediamine or urea). Thus 12 compounds were obtained that provedin vitroto possess high H1‐ and H2‐receptor antagonist activity at the isolated guinea‐pig ileum (H1) and the isolated guinea‐pig right atrium (H2), respectively. The incorporation of the diphenhydramine as well as the cyproheptadine component provides high affinity to H1‐receptors. The tricyclic cyproheptadine and its 10,11‐dihydro derivative (30–32, 34), however, cause a decrease of H2‐receptor antagonist potency compared to the diphenhydramines (29a—d, 33a—d). Using nitroethenediamine as the polar group is apparently more favourable to H1‐ and H2‐receptor affinity as the urea function. All compounds elicit a dual mode of competitive and noncompetitive antagonism. Among the novel compounds the nitroethenediamines with 4‐fluoro‐ or 4‐methyl‐substituted diphenhydramine as H1‐receptor antagonist moiety (29c, d) display the most potent H1‐ and H2‐receptor antagonist effects. The presented concept is a very promising way to combine H1‐ an

ISSN:0365-6233    

DOI:10.1002/ardp.19963290206

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

摘要:

AbstractA series of acyclic and heterocyclic analogues of carbacholine (1) was synthesized usingN‐methylcarbacholine (MCC,2),N,N‐dimethylcarbacholine (DMCC,3), and the corresponding tertiary amine (4) as leads. Whereas nicotinic acetylcholine receptor affinity was determined using [3H]nicotine as the radioactive ligand, [3H]oxotremorine‐M ([3H]Oxo‐M) and [3H]quinuclidinyl benzilate ([3H]QNB), in some cases supplemented with [3H]pirenzepine ([3H]PZ), were used as radioligands for muscarinic acetylcholine receptors on rat brain membranes. On the basis of receptor binding data, nicotinic/muscarinic (N/M) selectivity factors were determined, and muscarinic receptor efficacy (M agonist index) and M1selectivity (M2/M1index) estimated. In most cases, quaternized analogues showed higher affinity than the corresponding tertiary amines for muscarinic and, in particular, nicotinic receptor sites. Among the new compounds,N,N‐diethylcarbacholine (9e) (IC50= 0.046 μM), (S)‐1‐methyl‐2‐(N,N‐diethyl‐aminocarbonyloxymethyl)pyrrolidine (17k) (IC50= 0.068 μM), and the corresponding quaternized analogue,18k(IC50= 0.018 μM) showed the highest nicotinic receptor affinity. The tertiary amine,17kshowed much higher nicotinic receptor affinity than the acyclic analogue,4(IC50= 5.7 μM), and the N/M selectivity factor determined for17k(150) is an order of magnitude lower than that of nicotine (1400). The N/M selectivity factors for MCC (2) and DMCC (3), previously reported to be highly selective nicotinic receptor ligands, were shown to be 6.5 and 60, respectively, the latter value being compa

ISSN:0365-6233    

DOI:10.1002/ardp.19963290207

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

摘要:

AbstractA series of semirigid analogs of compounds1and2, two potent analgesics and cognition enhancers, have been synthesized and tested for antinociceptive activity (hot plate test) and for muscarinic affinity (binding in rat cerebral cortex). They were found to be in general less potent than the reference compounds; only one of them (22) shows a good affinity for the muscarinic receptor and an antinociceptive efficacy comparable with those of the reference compounds. At a dose of 30 mg/kg22is also able to reverse the amnesic effect of dicyclomine. Since the analgesic effect of these compounds is affected by the 5‐HT4antagonist SDZ 205557, the possible role of this receptor is discusse

ISSN:0365-6233    

DOI:10.1002/ardp.19963290208

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

ISSN:0365-6233    

DOI:10.1002/ardp.19963290201

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY