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Drug Nifedipine (drug + nifedipine)
Selected AbstractsSynthesis and calcium channel modulating effects of modified Hantzsch nitrooxyalkyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(pyridinyl or 2-trifluoromethylphenyl)-5-pyridinecarboxylatesDRUG DEVELOPMENT RESEARCH, Issue 4 2000Ramin Miri Abstract A group of racemic nitrooxyalkyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(pyridinyl or 2-trifluoromethylphenyl)-5-pyridinecarboxylates 8a,o were synthesized using modified Hantzsch reactions. In vitro calcium channel antagonist activities, determined using a guinea pig ileum longitudinal smooth muscle (GPILSM) assay, showed that compounds 8a,o exhibited weaker calcium antagonist activity (10,5 to 10,7 M range) than the reference drug nifedipine (IC50 = 1.43 × 10,8 M). Compounds 8 possessing a C-4 R1 = 2-pyridyl substituent were always more potent than the approximately equiactive analogs having an R1 = 3-pyridyl, 4-pyridyl or 2-CF3 -C6H4 -substituent, within each subgroup of nitrooxyalkyl compounds [R2 = , (CH2)nONO2 (n = 2, 3, 4) or ,CH(CH2ONO2)2]. Although the length of the R2 = ,(CH2)nONO2 substituent (n = 2,4) was not a determinant of smooth muscle calcium antagonist activity when the C-4 R1 -substituent was 2-pyridyl, when R1 was a 3-pyridyl, 4-pyridyl, or 2-CF3 -C6H4 -substituent, the relative potency order with respect to the R2 = ,(CH2)nONO2 substituent was n = 3 and 4 > n = 2. Replacement of the isopropyl substituent of the ester moiety of the calcium antagonist (±)-2-pyridyl 3a by a ,(CH2)nONO2 (n = 2,4) moiety increased calcium antagonist activity on GPILSM by 8-fold. In contrast, replacement of the isopropyl substituent of the ester moiety of the calcium agonists (±)-3-pyridyl 3b, (±)-4-pyridyl 3c or the methyl substituent of the ester moiety of Bay K8644 by a R2 nitrooxyalkyl substituent resulted in abolition of their calcium agonist effects on GPILSM that is replaced by a smooth muscle calcium antagonist effect. These calcium antagonist data support the concept that incorporation of a nitrooxyalkyl ester substituent constitutes a valuable drug design strategy to enhance Hantzsch 1,4-dihydropyridine calcium antagonist and/or abolish calcium agonist effects on smooth muscle. Replacement of the isopropyl (8b,c), or the methyl (8d) group by a ,CH2CH2ONO2 moiety resulted in retention of the cardiac positive inotropic effect where the relative potency order with respect to the C-4 substituent was 2-CF3 -C6H6 - (8d) > 3-pyridyl (8b) , 4-pyridyl (8c). Model hybrid (calcium channel modulation, ·NO release) compounds, that exhibit dual cardioselective agonist / smooth muscle selective antagonist activities, represent a novel type of 1,4-dihydropyridine CC modulator that offers a potential approach to drug discovery targeted toward the treatment of congestive heart failure and for use as probes to study the structure,function relationship of calcium channels. Drug Dev. Res. 51:225,232, 2000. © 2001 Wiley-Liss, Inc. [source] Hantzsch 1,4-dihydropyridines containing a nitrooxyalkyl ester moiety to study calcium channel antagonist structure,activity relationships and nitric oxide releaseDRUG DEVELOPMENT RESEARCH, Issue 4 2000Jeffrey-Tri Nguyen Abstract A group of 3-nitrooxyalkyl 5-alkyl 1,4-dihydro-2,6-dimethyl-4-(pyridyl)-3,5-pyridinedicarboxylates were prepared using a modified Hantzsch reaction that involved the condensation of a nitrooxyalkyl acetoacetate with an alkyl 3-aminocrotonate and a pyridinecarboxaldehyde. 1H NMR nuclear Overhauser enhancement (nOe) studies for 3-(3-nitrooxypropyl) 5-isopropyl 1,4-dihydro-2,6-dimethyl-4-(2-pyridyl)-3,5-pyridinedicarboxylate (17) indicates a predominant rotamer exists in solution where the pyridyl nitrogen atom is orientated above the 1,4-DHP ring system, and the pyridyl nitrogen atom is antiperiplanar to the 1,4-DHP ring H-4 proton. Variable temperature 1H NMR studies (,30 to +60°C) showed the 1,4-DHP NH proton in 17 is H-bonded in CHCl3 solution. This interaction is believed to be due to intermolecular H-bonding between the pyridyl nitrogen free electron pair and the 1,4-DHP NH proton. In vitro calcium channel antagonist (CCA) activities were determined using a muscarinic-receptor-mediated Ca+2 -dependent contraction of guinea pig ileal longitudinal smooth muscle assay. This class of compounds exhibited lower CCA activity (IC50 = 5.3 × 10,6 to 3.5 × 10,8 M range) than the reference drug nifedipine (IC50 = 1.4 × 10,8 M). For compounds having C-3 ,CH2CH2ONO2 and C-4 pyridyl substituents, the C-5 alkyl was a determinant of CCA (i -Pr > the approximately equipotent i -Bu, t -Bu, and Et analogs). The point of attachment of the isomeric C-4 pyridyl substituent was a determinant of CCA when C-3 ,CH2CH2ONO2 and C-5 i -Pr substituents were present providing the potency profile 2-pyridyl , 3-pyridyl > 4-pyridyl. CCA with respect to the C-3 nitrooxyalkyl substituent was inversely dependent on the length of the alkyl spacer. The percent nitric oxide (·NO) released in vitro by this group of compounds (range of 0.03,0.43%/ONO2 group), quantified as nitrite by reaction with the Griess reagent, was lower than that for the reference drug glycerol trinitrate (3.81%/ONO2 group). Nitric oxide release studies showed that the %·NO released was dependent on the number of ONO2 groups/molecule. A QSAR study for this group of compounds showed a correlation between the specific polarizability descriptor (SpPol) and %·NO release. Drug Dev. Res. 51:233,243, 2000. © 2001 Wiley-Liss, Inc. [source] Synthesis of alkyl 6-methyl-4-(2-pyridyl)-1,2,3,4-tetrahydro-2H -pyrimidine-2-one-5-carboxylates for evaluation as calcium channel antagonistsJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 3 2007Kuljeet Kaur The Bigenelli acid catalyzed condensation of 2-pyridylcarboxaldehyde (1), urea (2) and an alkyl acetoacetate (3) afforded the respective alkyl (Me, Et, i -Pr, i -Bu, t -Bu) 6-methyl-4-(2-pyridyl)-1,2,3,4-tetrahydro-2H -pyrimidine-2-one-5-carboxylates (4a-e). The most potent calcium channel antagonist ethyl 6-methyl-4-(2-pyridyl)-1,2,3,4-tetrahydro-2H -pyrimidine-2-one-5-carboxylate (4b, IC50 = 1.67 × 10,5 M) wasa much weaker calcium channel antagonist than the reference drug nifedipine (Adalat®, IC50 = 1.40 × 10,8 M) on guinea pig ileal longitudinal smooth muscle (GPILSM). The alkyl 6-methyl-4-(2-pyridyl)-1,2,3,4-tetrahydro-2H -pyrimidine-2-one-5-carboxylates did not show any inotropic effect on heart since no increase, or decrease, in the contractile force of guinea pig left atrium was observed. These structure activity studies show that the alkyl 6-methyl-4-(2-pyridyl)-1,2,3,4-tetrahydro-2H -pyrimidine-2-one-5-carboxylates (4a-e) are partial bioisosteres of nifedipine with respect to calcium channel antagonist activity on guinea pig ileal longitudinal smooth muscle (GPILSM). [source] The effect of whole-body sunbed ultraviolet A exposure on the pharmacokinetics of the photolabile drug nifedipinePHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, Issue 3 2000H. S. Al-Ajmi The calcium antagonist nifedipine absorbs ultraviolet A (UVA) radiation and readily photodegrades in vitro to a toxic nitroso-pyridine photoproduct. We examined whether whole body exposure of normal subjects to sunbed UVA radiation would affect the pharmacokinetics of nifedipine. Eight healthy, male, Caucasian volunteers (phototypes I,III) participated in this ethically approved, randomised, cross-over study. Each subject attended on 2 occasions, one week apart, and on each occasion was given a single oral dose (10 mg) of nifedipine following which blood samples were collected at 0, 0.5, 1. 1.5, 2, 2.5, 3, 3.5, 4, 5, 6 and 7 h. During one of the visits, 15 min after nifedipine ingestion, a whole-body UVA (sunbed comprising Philips R-UVA lamps) dose of 70% of the individual's predetermined minimal phototoxic dose was delivered over a period of 17,36 min. Plasma nifedipine levels were measured using a standard reverse-phase high-performance liquid chromatography method. The area under the plasma concentration-time curve (AUC) of nifedipine during the UVA irradiation session (median 206 ng,·,ml,1,·,h,1) was significantly higher than during the non-irradiation control session (median 174.5 ng,·,ml,1,·,h,1) (P=0.03; 95% C.I. for difference in medians 9.9 to 55.9 ng,·,ml,1,·,h,1). UVA irradiation did not significantly affect any of the other measured pharmacokinetic parameters (Cmax, t1/2, tmax). We demonstrate that sunbed UVA irradiation does not lead to in vivo photodegradation of nifedipine in healthy humans after a single dose. The apparent increase in AUC during UVA irradiation may be due to slightly slower metabolism of nifedipine in the presence of toxic photoproduct(s) or due to blood distribution changes affecting liver blood flow. [source] | ||||||||||