- DIPEPTIDYL PEPTIDASE-IV INHIBITORS
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The present invention relates generally to pyrrolidine and thiazolidine DPP-IV inhibitor compounds. The present invention also provides synthetic methods for preparation of such compounds, methods of inhibiting DPP-IV using such compounds and pharmaceutical formulations containing them for treatment of DPP-IV mediated diseases, in particular, Type-2 diabetes.
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Page/Page column 62
(2008/06/13)
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- New Triazine Derivatives as Potent Modulators of Multidrug Resistance
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A series of 70 triazine derivatives have been synthesized and tested for their capacity to modulate multidrug resistance (MDR) in DC-3F/AD and KB-A1 tumor cells in vitro, in comparison with verapamil (VRP), a calcium channel antagonist currently used in therapy as an antihypertensive drug, which also shows MDR modulating activity.Among the 12 selected compounds, 16 (S9788) showed high MDR reversing properties in vitro (300- and 6-fold VRP at 5μM in DC-3F/AD and KB-A1 cells, respectively) and induced a strong accumulation of adriamycin.The relationship between the increase of ADR accumulation and the fold reversal induced by these compounds and their lack of effects on the sensitive DC-3F cells suggest that they act mainly by inhibiting the P-glycoprotein (Pgp) catalyzed efflux of cytotoxic agents, as already described for a majority of MDR modulators.In vivo, in association with the antitumor drug vincristine (0.25 mg/kg), 16 (100 mg/kg) increased the T/C by 39percent in mice bearing the resistant tumor cell line P388/VCR.According to these interesting properties, 16 was selected for a clinical development because it is more bioavailable than 34, even though it was less active.
- Dhainaut, Alain,Regnier, Gilbert,Atassi, Ghanem,Pierre, Alain,Leonce, Stephane,et al.
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p. 2481 - 2496
(2007/10/02)
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- N-SUBSTITUTED DERIVATIVES OF 6,11-DIHYDRODIBENZOTHIEPIN-11-AMINE AND RELATED COMPOUNDS; SYNTHESIS AND PHARMACOLOGICAL SCREENING
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Reactions of N-(6,11-dihydrodibenzothiepin-11-yl)chloroacetamide (II) with dimethylamine, morpholine, and 2-(1-piperazinyl)ethanol afforded the amino amides III-V.Substitution reactions of 11-chloro-6,11-dihydrodibenzothiepin with ethylenediamine and N,N-dimethylethylenediamine gave the diamines VI and VII. 6,11-Dihydrodibenzothiepin-11-amine (I) was treated with ethyl chloroacetate and ethyl 2-bromopropionate to give the amino esters X and XI which were transformed on the one hand to the acids VIII and IX, and to the amides XII and XIII on the other.(6,11-Dihydrodibenzothiepin-11-yl)methylamine (XVIa) and (10,11-dihydro-5H-dibenzocycloheptene-5-yl)methylamine (XVIb) were transformed via the chloroacetamides XVIIa and XVIIb to the (4-methyl-1-piperazinyl)acetamides XVa and XVb.Compound V showed local anaesthetic and antiarrhytmic activity, the diamine VII had antihistamine and antireserpine effects, the amide XII was found to be an anticonvulsant, and the piperazines XVa and XVb inhibited effectively the formation of the indomethacin-induced gastric ulcers in rats.
- Valenta, Vladimir,Hulinska, Hana,Holubek, Jiri,Dlabac, Antonin,Metys, Jan,et al.
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p. 860 - 869
(2007/10/02)
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- N6-(arylalkyl)adenosines. Identification of N6-(9-fluorenylmethyl)adenosine as a highly potent agonist for the adenosine A2 receptor.
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Several N6-(arylalkyl)adenosines related to N6-benzyladenosine were synthesized, and their A1 and A2 adenosine receptor binding affinities were determined. The annulated derivative N6-(1-naphthylmethyl)adenosine resulted in a very potent A2 agonist (A1 Ki = 24 nM, A2 Ki = 9.1 nM), whereas N6-(9-anthracenylmethyl)adenosine was virtually inactive (A1 Ki = 9,000 nM, A2 Ki = 29,000 nM). Interestingly, the structurally similar N6-(9-fluorenylmethyl)adenosine was the most potent A2 agonist reported to date, with a Ki of 4.9 nM in A2 binding and 5.1 nM in A1 binding. The homologues N6-9-fluorenyladenosine and N6-[2-(9-fluorenyl)ethyl]adenosine showed little or no activity at either adenosine receptor. Effects of these agents on heart rate and coronary flow in the isolated rat heart paralleled their A1 and A2 binding affinities, respectively. These data suggest that for high affinity at the A2 receptor a planar hydrophobic function at a certain distance and angle from the N6 nitrogen is required.
- Trivedi,Bristol,Bruns,Haleen,Steffen
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p. 271 - 273
(2007/10/02)
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