RT Journal Article
SR Electronic
T1 Pharmacological Characterization of 2NTX-99 [4-Methoxy-N1-(4-trans-nitrooxycyclohexyl)-N3-(3-pyridinylmethyl)-1,3-benzenedicarboxamide], a Potential Antiatherothrombotic Agent with Antithromboxane and Nitric Oxide Donor Activity in Platelet and Vascular Preparations
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 830
OP 837
DO 10.1124/jpet.105.097170
VO 317
IS 2
A1 Carola Buccellati
A1 Angelo Sala
A1 Giuseppe Rossoni
A1 Valérie Capra
A1 G. Enrico Rovati
A1 Antonio Di Gennaro
A1 Giancarlo Folco
A1 Susanna Colli
A1 Cesare Casagrande
YR 2006
UL http://jpet.aspetjournals.org/content/317/2/830.abstract
AB Thromboxane (TX) A2, prostacyclin (PGI2), and nitric oxide (NO) regulate platelet function and interaction with the vessel wall. Inhibition of TXA2, implemented synthesis of PGI2, and supply of exogenous NO may afford therapeutic benefit. 2NTX-99 [4-methoxy-N1-(4-trans-nitrooxycyclohexyl)-N3-(3-pyridinylmethyl)-1,3-benzenedicarboxamide], a new chemical entity related to picotamide, showed antithromboxane activity and NO donor properties. 2NTX-99 relaxed rabbit aortic rings precontracted with norepinephrine or U46619 (9,11-dideoxy-9α,11α-methanoepoxy-prosta-5Z,13E-dien-1-oic acid; EC50, 7.9 and 17.1 μM, respectively), an effect abolished by 10 μM 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ). 2NTX-99 inhibited arachidonic acid (AA)-induced washed platelet aggregation (EC50, 9.8 μM) and TXB2 formation (-71% at 10 μM), and its potency increased in the presence of aortic rings (EC50, 1.4 μM). In whole rabbit aorta incubated with homologous platelets, AA caused contraction and TXA2 formation, reduced by 2NTX-99 (10-40 μM): contraction, -28 and -47%, TXA2 formation, -37 and -75.4%, respectively, with concomitant increase in PGI2. 2NTX-99 (20-40 μM) inhibited U46619-induced aggregation in rabbit platelet-rich plasma (PRP) (-74 ± 6.7 and -96 ± 2.4%, respectively) and inhibited collagen-induced aggregation in human PRP (-48.2 ± 10 and -79.2 ± 6%), whereas ozagrel was ineffective. In human embryonic kidney 293 cells transfected with the TXA2 receptor isophorm α receptor, 2NTX-99 did not compete with the ligand, [3H]SQ29,548 ([3H][1S-[1α,2β(5Z),3β,4α]]-7-[3-[[2-(phenylamino)-carbonyl]hydrazino]methyl]-7-oxabicyclo[2,2,1]-hept-2-yl]-5-heptanoic acid), or prevent inositol phosphate accumulation. After oral administration (50-250 mg/kg), 2NTX-99 inhibited TXA2 production in rat clotting blood (-71 and -91%); at 250 mg/kg, an area under the curve, 0 to 16 h, of 149.5 h/μg/ml and a t1/2 of 6 h were calculated, with a Cmax value of 31.8 ± 8.2 μg/ml. An excellent correlation between plasma concentrations and TXA2 inhibition occurs. 2NTX-99 controls platelet function and vessel wall interaction by multifactorial mechanisms and possesses therapeutic potential. The American Society for Pharmacology and Experimental Therapeutics