Synthesis and calcium channel modulating effects of modified Hantzsch nitrooxyalkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(pyridinyl or 2‐trifluoromethylphenyl)‐5‐pyridinecarboxylates

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.     

Syntheses,calcium channel modulation effects,and nitric oxide release studies of O2‐alkyl‐1‐(pyrrolidin‐1‐yl) diazen‐1‐ium‐1,2‐diolate 4‐aryl(heteroaryl)‐1,4‐dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxylates

A group of racemic 4‐aryl(heteroary)‐1,4‐dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxy‐lates possessing a potential nitric oxide donor C‐5 O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester [alkyl=(CH₂)_n, n=1–4] substituent were synthesized using a modified Hantzsch reaction. Compounds having a C‐4 2‐trifluoromethylphenyl ( 16 ), 2‐pyridyl ( 17 ), or benzofurazan‐4‐yl ( 20 ) substituent generally exhibited more potent smooth‐muscle calcium channel antagonist activity (IC₅₀ values in the 0.55 to 38.6 μM range) than related analogs having a C‐4 3‐pyridyl ( 18 ), or 4‐pyridyl ( 19 ) substituent with IC₅₀ values > 29.91 μM, relative to the reference drug nifedipine (IC₅₀=0.0143 μM). The point of attachment of C‐4 isomeric pyridyl substituents was a determinant of antagonist activity where the relative potency profile was 2‐pyridyl > 3‐pyridyl and 4‐pyridyl. Subgroups of compounds 16a–d , 17a–d , and 20a–d having alkyl spacer groups of variable chain length [–CO₂(CH₂)_nO–, n=1–4] exhibited small differences in calcium channel antagonist potency. Replacement of the ester “methyl” moiety of Bay K 8644 by an O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate group provided the Bay K 8644 group of analogs 16a‐d that retained the desired cardiac positive inotropic effect. The most potent compound in this group, O²‐ethyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(2‐trifluoromethylphenyl)pyridine‐5‐carboxylate ( 16b , EC₅₀=0.096 μM) is about eightfold more potent positive inotrope (cardiac calcium channel agonist) than the reference compound Bay K 8644 (EC₅₀=0.77 μM). A similar replacement of the ester “isopropyl” group in the C‐4 benzofurazan‐4‐yl group of compounds by an O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester substituent provided compounds 20 (n=1 and 4) that were approximately equipotent cardiac positive inotropes with the parent reference compound PN 202‐791 ( 3 , EC₅₀=9.40 μM). The O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester moiety present in 1,4‐dihydropyridine calcium channel modulating compounds 16–20 is not a suitable ?NO donor moiety because the percent nitric oxide released upon in vitro incubation with either l ‐cysteine, rat serum, or pig liver esterase was less than 1%. Drug Dev. Res. 60:204–216, 2003. © 2003 Wiley‐Liss, Inc.     

Synthesis,Evaluation of Pharmacological Activities and Quantitative Structure–Activity Relationship Studies of a Novel Group of bis(4‐Nitroaryl‐1,4‐dihyropyridine)

Voltage‐dependent calcium channels are crucial targets for a wide range of clinically active pharmacological agents. From these agents, 1,4‐dihydropyridines constitute a group of small organic compounds are based on a core pyridine structure which can both block and enhance calcium currents. They are considered specific for L‐Type calcium channels; however, other channel types, and in particular certain T‐Type channels, may show sensitivity to dihydropyridine compounds. In this study, we synthesized a novel group of bis‐1,4‐dihydropyridines using the procedure reported by Dagnino that involved the condensation of n‐alkyl diacetoacetate (n = 2–7) with methyl‐3‐aminocrotonate and nitrophenylaldehyde. The synthesis was run under two conditions: (i) reflux and (ii) microwave. Calcium channels antagonist activity were determined in vitro using guinea‐pig ileum longitudinal smooth muscle assay. Synthesis of these compounds was confirmed with 1H‐NMR, IR and mass spectrometry. Then IC₅₀ of them are calculated and compared with Nifedipine. Finally, the result of this pharmacological assay was used in quantitative structure–activity relationship studies utilizing multiple linear regression analysis. Most of these compounds are less active compared with Nifedipine. Decrease in activity is the result of increase in steric hindrance. The quantitative structure–activity relationship study indicates that the activity is related to the electrostatic and topological parameters and the distance between two C5‐esteric groups of 1,4‐dihydropyridine rings.     

Synthesis and Positive Inotropic Evaluation of 2‐(4‐(4‐Substituted benzyloxy)‐3‐methoxybenzyl)‐1,4‐diazepan‐1‐yl)‐N‐(4,5‐dihydro‐1‐methyl[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)‐acetamides

In an attempt to search for more potent positive inotropic agents, a series of 2‐(4‐(4‐substituted benzyloxy)‐3‐methoxybenzyl)‐1,4‐diazepan‐1‐yl)‐N‐(4,5‐dihydro‐1‐methyl[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)acetamides was synthesized and their positive inotropic activities were evaluated by measuring left atrium stroke volume on isolated rabbit‐heart preparations. Several compounds showed favorable activity compared with the standard drug Milrinone among which 2‐(4‐(4‐(2‐chlorobenzyloxy)‐3‐methoxybenzyl)‐1,4‐diazepan‐1‐yl)‐N‐(4,5‐dihydro‐1‐methyl‐[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)acetamide 6e was found to have the most desirable potency with the 6.79 ± 0.18% increased stroke volume (Milrinone: 1.67 ± 0.64%) at a concentration of 1×10^–5 M in our in‐vitro study. The chronotropic effects of those compounds having inotropic effects were also evaluated in this work.     

Structure–activity relationship of [Nphe1]‐NC‐(1‐13)‐NH2, a pure and selective nociceptin/orphanin FQ receptor antagonist

Abstract: A series of analogs of the ORL1 receptor antagonist [Nphe¹]‐NC(1‐13)‐NH₂ was prepared and tested for agonistic and antagonistic activities in the mouse vas deferens, a preparation that shows high sensitivity to nociceptin and related peptides. The purpose of this study was to determine the role of the aromatic residue at the N‐terminal for antagonism and eventually identify compounds with improved potency. Results indicated that all 23 compounds are inactive as agonists, and the antagonistic potency of the initial template [Nphe¹]‐NC(1‐13)‐NH₂ is high (pK_B 6.43) compared with those of all other compounds except [(S)(βMe)Nphe¹]NC(1‐13)‐NH₂ (pK_B 6.48). The other 22 compounds can be divided into two groups: 10 show antagonistic potencies (pK_B) ranging from 5.30 to 5.86, whereas the other 12 compounds are inactive. This study clearly shows that the aromatic ring of Nphe is very critical for the interaction with the ORL1 receptor and can not be enlarged or sterically modified without significant loss of antagonistic potency.