摘要:

AbstractThis paper presents the synthesis of new indole, pyridazino[4,5‐b]indole, and pyridazino[4,5‐a]indole analogs as well as a study of their “in vitro” activity as inhibitors of different phosphodiesterases isolated from dog cardiac tissue, dog aorta, and bovine platelets; the study of their activity as inhibitors of platelet aggregation in guinea pig whole blood, with ADP and arachidonic acid (AA) as pro‐aggregants, is also included. The selected compounds 8‐benzyloxy‐3,4‐dihydro‐1‐(3,4,5‐trimethoxy)benzylideneaminopyridazino[4,5‐b]indole14g, and 8‐benzyloxy‐4‐[(3,5‐dimethyl)pyrazolyl]pyridazino[4,5‐b]indole20present an interesting profile as potential inodilators, with a complementary, beneficial activity as inhibitors of the aggregation, activities which could possibly be related to the inhibition of the PDE's. Among the other compounds studied, 8‐benzyloxy‐3,4‐dihydro‐1‐[4‐(methyl)piperazino]acetamidopyridazino[4,5‐b]indol‐4‐one16cand 8‐benzyloxy‐3,4‐dihydro‐1‐[4‐(2‐methoxyphenyl)piperazino]acetamidopyridazino[4,5‐b]indol‐4‐one16fstood out as inhibitors of platelet aggrega

ISSN:0365-6233    

DOI:10.1002/ardp.19953281002

出版商:WILEY‐VCH Verlag    

年代:1995

数据来源: WILEY

摘要:

AbstractWith the goal of obtaining inexpensive yet potent anti‐AIDS drugs, simple inhibitors of HIV‐1 protease were synthesised. The C2‐symmetrical pseudopeptidic substrate analogues can be prepared as inhibitors for HIV‐1 protease starting from symmetrical ketones3a–dby a facile four‐step synthesis. After bromination of3a–dto α,α′‐dibromoketones4a–d, we synthesised the diamino compounds6a–cby Gabriel synthesis, which were then coupled with Z‐valine to yield inhibitors with a central keto group2a–c. We also synthesised inhibitors including a central hydroxy group8a‐d a‐iby azidation, reduction with LiAlH4and coupling of the β,β′‐diaminohydroxy compounds with appropriate peptides. The first set of compounds showed only weak inhibition whereas the

ISSN:0365-6233    

DOI:10.1002/ardp.19953281003

出版商:WILEY‐VCH Verlag    

年代:1995

数据来源: WILEY

摘要:

AbstractA number of 2‐{[(phenoxy or phenyl)acetyl]amino}benzoic acid derivatives were prepared in about 50% yield from (phenoxy or phenyl)acetyl chloride and anthranilic acid derivatives. All the compounds were tested asin vitroinhibitors of 3α‐hydroxysteroid dehydrogenase, since enzyme inhibition predicts potential antiinflammatory activityin vivoThe most active compounds3 1, m, sare about 3.5 times more active than acetylsalicylic acid (ASA). Activity is influenced by electronic as well as steric eff

ISSN:0365-6233    

DOI:10.1002/ardp.19953281004

出版商:WILEY‐VCH Verlag    

年代:1995

数据来源: WILEY

摘要:

AbstractA series of new positive inotropic agents was synthesized with the aim of combining the pharmacophores of the imidazolone‐type phosphodiesterase (PDE) inhibitor enoximone and guanidine‐type histamine H2receptor agonists such as arpromidine. All compounds arepara‐substituted 4‐benzoyl‐5‐alkyl‐2‐imidazolones. H2agonism was incorporated byp‐(hetero)arylalkyl substituents, in particular by an imidazolylpropyl guanidine group. In addition analogous ureas, cyanoguanidines, alkyl guanidine carboxylates, and amides were prepared. These functional groups were either directly attached to the phenyl ring or linked by an appropriate spacer. The compounds were screened for positive inotropic activity in the isolated electrically stimulated guinea pig papillary muscle and for inhibition of PDE III (cGMP‐inhibited cAMP PDE, isolated from guinea pig heart). The cardiotonics obtained proved to be either PDE III inhibitors, some of them surmounting up to 3‐fold the potency of enoximone, or pharmacological hybrids combining both PDE III inhibitor and histamine H2receptor agonist activities. These hybrids were the most potent positive inotropic substances at the papillary muscle, probably due to their synergistic mechanism of action. The participation of histamine H2receptors could be demonstrated in the papillary muscle preparation by pretreatment with the H2antagonist famotidine (10 μM) as well as by further pharmacological experiments using isolated perfused hearts of guinea pigs and rats, isolated guinea pig right atria, adenylyl cyclase and H2receptor binding assays. At equieffective concentrations the moderate PDE III inhibitor and histamine H2agonistN1‐{4‐[(1,3‐dihydro‐5‐methyl‐2‐oxo‐3H‐imidazol‐4‐yl)‐carbonyl]phenyl}‐N2‐[3‐(1H‐imidazol‐4‐yl)propyl]guanidine65and the 5‐ethyl homologue66were about 2 and 10 times more potent than enoximone at the papillary muscle. Moreover, both compounds produced a

ISSN:0365-6233    

DOI:10.1002/ardp.19953281005

出版商:WILEY‐VCH Verlag    

年代:1995

数据来源: WILEY

摘要:

AbstractTriterpene and steroid saponins and sapogenins of medicinal plants (Aesculus hippocastanumL.,Hedera helixL.,Ruscus aculeatusL.) are claimed to be effective for the treatment/prevention of venous insufficiency. In this work we evaluated the inhibitory effects of these plant constituents on the activity of elastase and hyaluronidase, the enzyme systems involved in the turnover of the main components of the perivascular amorphous substance.The results evidence that forHedera helixL., the sapogenins only non‐competitively inhibit hyaluronidase activity in a dose‐dependent fashion, showing comparable IC50values (hederagenin IC50= 280.4 μM; oleanolic acid IC50= 300.2 μM); both the saponins hederacoside C and α‐hederin are very weak inhibitors.The same behaviour is observed for serine protease porcine pancreatic elastase: the glycosides are devoid of inhibitory action, while genins are potent competitive inhibitors (oleanolic acid IC50= 5.1 μM; hederagenin IC50= 40.6 μM). Constituents fromAesculus hippocastanumL. show inhibitory effects only on hyaluronidase, and this activity is mainly linked to the saponin escin (IC50= 149.9 μM), less to its genin escinol (IC50= 1.65 μM).By contrast, ruscogenins fromRuscus aculeatusL., ineffective on hyaluronidase activity, exhibit remarkable anti‐elastase activity (IC50= 119.9 μM; competitive inhibition). The mechanism of elastase inhibition by triterpene and steroid aglycones, with a nitroanilide derivative as substrat

ISSN:0365-6233    

DOI:10.1002/ardp.19953281006

出版商:WILEY‐VCH Verlag    

年代:1995

数据来源: WILEY

摘要:

AbstractA new C50‐hydroperoxide (1) with a hitherto unknown constitution, containing cadinane hydroperoxide and hyperforin (2) as partial structures, was isolated from the stems and leaves of St. John's wort (Hypericum perforatumL., Hypericaceae). The structure was elucidated by high‐resolution NMR techniques (1D and 2D NMR experimen

ISSN:0365-6233    

DOI:10.1002/ardp.19953281007

出版商:WILEY‐VCH Verlag    

年代:1995

数据来源: WILEY

摘要:

AbstractThe title compound9, which is a prodrug, and its active metabolite7were labelled with131I (7*/9*) to investigate their pharmacokinetic behaviour, including the distribution between stomach, gut, muscle, blood, lung, liver, kidney, adrenal gland, heart, and spleen. Four hours after oral administration of7* to mice only 3% of the dose had been absorbed from the g.i. tract. After 24 h 54 % of the radioactivity still is found the gut, predominantly in the small intestine. These results explain why7, which is a potent antiplatelet drugin vitro, shows no antithrombotic effectin vivo. In contrast, the produg9/9* is absorbed considerably, i.e. up to 50 % in 4 h from the g.i. tract depending on the dose applied and the vehicle used. At doses in the micromolar range the absorption appears to be diffusion limited. The highest concentrations are found in the liver and the kidneys suggesting a first pass effect of7followed by renal excretion. From the blood levels achieved, the dose nessessary for an antithrombotic effect has been calculated to be about 100 mg/kg. In summary, theN‐ethoxycarbonyl derivatives of oligoamines appear to be suitable prodrugs for oral administration of oligoamine

ISSN:0365-6233    

DOI:10.1002/ardp.19953281008

出版商:WILEY‐VCH Verlag    

年代:1995

数据来源: WILEY

摘要:

AbstractIsovanillin was oxidized with magnesium monoperoxyphthalate to 4‐methoxyresorcinol (2) and the latter was reacted with 3‐oxopropionic acid ethylester preparedin situto give scopoletin (1). These reactions can be achieved in kg scale in high yie

ISSN:0365-6233    

DOI:10.1002/ardp.19953281009

出版商:WILEY‐VCH Verlag    

年代:1995

数据来源: WILEY

ISSN:0365-6233    

DOI:10.1002/ardp.19953281011

出版商:WILEY‐VCH Verlag    

年代:1995

数据来源: WILEY

ISSN:0365-6233    

DOI:10.1002/ardp.19953281001

出版商:WILEY‐VCH Verlag    

年代:1995

数据来源: WILEY