synthesis and in vitro pharmacology of a series of histamine h2 ...

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Chapter 7 The histamine H 2 chronotropic and inotropic activities of type A hybrid molecules with an ethyl chain length cannot be determined because of the negative inotropic and chronotropic effects exhibited by the DHP structural moiety. This complicated attribution on overall inotropic activity makes it impossible to verify the contribution of phenyl ring substituents, as described by Rodenkirchen et al. 29 . They demonstrated that in a series of nifedipine analogues, the negative inotropic activity on cat papillary muscle mainly depends on steric and lipophilic substituent properties for aryl derivatives and/or on the steric nature of the ester substituents. Bulky ester substituents decrease the negative inotropic activities in cat papillary muscle. In general the negative inotropic activity of phenyl substituted DHP derivatives decrease in the order of ortho > meta > para substitution. These structure-activity relationship studies are confirmed by Boyd et al. 30 , who used rabbit papillary muscle. The in vitro and in vivo pharmacology of a series of felodipine (ethyl methyl 4-(2,3dichlorophenyl)-2,6-dimethyl-l,4-dihydropyridine-3,5-dicarboxylate) analogues with different ester groups in 3- and 5-position on the DHP ring have been evaluated on rat papillary muscle and portal vein, leading to the conclusion that the DHP effector site in vascular smooth muscle must be structurally different from the DHP effector site in cardiac tissue 31 . Type B hybrid molecules have much lower calcium channel blocking activities than type A hybrid molecules. The explanation of the lower calcium channel blocking activities can be reduced to the discussion on the structure activity relationship of the tiamdipine analogues from table I and the 4-(co-substituted-alkoxy)phenyl DHPs from table VI. In general, calcium channel blocking activity decreases for 4-(substitutedphenyl)-l,4-DHPs in the order of ortho > meta > para substitution, and this effect becomes more pronounced when the substituent becomes bulkier. This might explain the reduction of calcium channel blocking activity of type B hybrid molecules with increasing alkyl substituents on the 4-phenyl ring, although this is not confirmed by the radioligand binding studies. In a patent concerning a series of type C hybrid molecules, Schickaneder et al. 24 have claimed that the compound with a hexyl chain, a methyl ester, and a 3-nitro substituent on the 4-phenyl, is a potent histamine H2-agonist (pD2 = 7.4) and calcium channel blocker (pA2 = 7.0). Unfortunately, no pharmacological methods are described, making it impossible to compare the activities of type C hybrid molecules with those of type A and B hybrid molecules. Furthermore, it is not clear whether the authors of type C hybrid molecules have encountered the same problems in determining the individual actions of the two pliarmacophoric groups. 5 Conclusion Of the proposed type A and B hybrid molecules combining histamine H2-agonistic properties and calcium channel blocking activities, the type A hybrid molecule VUF 4575 is the most promissing compound which could provide interesting leads in the treatment of myocardial heart failure or some hypertensive disorders, because it combines good in vitro Ca 2+ -blocking action and an overall positive inotropic and 180
Chapter 7 chronotropic activity in one molecule. VUF 4573 has a nearly equivalent histamine H2-agonistic potency as VUF 4575, but has a lower calcium channel blocking activity. Introduction of an imidazolylpropylguanidine structure on the 4-phenyl ring on the DHP structural moiety (type B hybrid molecules) affords VUF 4730 which exhibits both overall positive chronotropic and inotropic activity, but is less interesting than VUF 4575 or VUF 4573 because it has a lower calcium channel blocking activity. Experimental protocols If indicated crude reaction products were purified by flash chromatography on silicagel (J.T.Baker 70242). Melting points were determined on a Mettler FP 52 with microscope. !H-NMR and 13 C-NMR-spectra were recorded on a Bruker AC 200. The chemical shifts are in ppm relative to tetramethylsilane. 13 C-NMR-spectra were verified by CH-cosy NMR experiments. Mass spectra were determined on a Mat 90 (Finnigan Mat) mass spectrometer with Fast Atom Bombardment ionisation (matrix: glycerol + ammonium acetate, thioglycerol or 3-nitrobenzylalcohol, Ion Tech saddlefield gun, 8 keV Xenon with xenon ioncurrent 0.2 mA). All compounds gave the expected (M+H)+ and to a lesser extend (M-H) - peaks (negative ions). Furthermore the purity of the compounds was checked by thin layer chromatography (Merck silica gel 60, F254 0.25 mm). General synthetic procedure Diethyl 2-[(6-aminohexyl)thiomethyl]-6~methyl-4-(3-nitrophenyl)-l^ pyridine-3 yS-dicarboxylate fumarate VUF 4731 VUF 4731 was synthesized according to VUF 9159 as decribed previously in chapter 5 (this thesis). Yield = 24% (starting from diethyl 2-chloromethyl-6-methyl-4-(3-nitrophenyl)-l,4- dihydropyridine-3,5-dicarboxylate); melting point = 98.4-100.1°C. Mass spectrum, glycerol + ammonium acetate as matrix (FAB + ) 506 [M+H} + , (FAB) 504 [M-H]". ^-NMR (DMSO-d 6): 1.11-1.65 ppm (m, 14H, 2x C// 3-CH 2-0 and S-C-(C// 2) 4-C-N), 2.32 ppm (s, 3H, pyridine-C// 3), 2.44-2.56 ppm (m, 2H, C// 2), 2.73-2.78 ppm (m, 2H, C// 2), 3.70 and 4.09 ppm (AB, = 13.1 Hz, 2H, pyridine-C// 2-S), 3.98-4.05 ppm (m, 4H, 2x CH 3-O/ 2-0), 5.01 ppm (s, 1H, pyridine-// 4), 6.48 ppm (s, 2H, fumaric acid-C//), 7.52-8.02 ppm (m, 6.5H, 4x phenyl-// and N// 2), 9.36 ppm (bs, 1H, pyridine-N//). 13 C-NMR (DMSO-d6): 13.73 and 13.83 ppm (q, 2x CH 3-CH 2-0), 18.00 ppm (q, pyridine-CH 3), 25.20 and 26.74 and 27.57 and 28.87 and 29.14 and 30.85 ppm (t, S- (CH 2) 6-N), 38.28 ppm (t, pyridine-CH 2-S), 39.06 ppm (d, pyridine-C 4), 59.05 and 59.33 ppm (t, 2x CH 3-CH 2-0), 100.26 and 101.36 ppm (s, pyridine-C 3 and C 5), 120.99 and 121.66 and 129.30 and 133.93 ppm (d, 4x phenyl-CH [C 2, C 4, C 5, C 6]), 134.98 ppm (d, fumaric acid CH), 146.53 and 147.25 and 147.69 and 149.74 ppm (s, phenyl- C x and C 3 and pyridine-C 2 and C 6), 165.92 and 166.15 ppm (s, 2x carbonyl-C), 167.91 ppm (s, 2x carbonyl-C fumaric acid). 181
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SYNTHESIS AND IN VITRO PHARMACOLOGY
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Promotor : prof.dr H. Timmerman Cop
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The investigations described in thi
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Chapter 1 Chapter 1 Pharmacotherape
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Chapter 1 2.2 Role of calcium Calci
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Chapter 1 The excitation-contractio
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Chapter 1 Antiarrhythmic drugs modi
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Chapter 1 Until now, no selective c
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Chapter 1 pyridines are expected to
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Chapter 1 Like the p-adrenoceptor s
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Chapter 1 3.3.3 Phosphodiesterase I
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arteries brain Central Nervous Syst
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Chapter 1 The development of renin
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^-ADRENOCEPTOR ANTAGONISTS Chapter
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51 Cromakalim 52 Nicorandil 53 Pina
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Chapter 1 The CCBs are a heterogene
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Chapter 1 4.2 Combination of cardio
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Chapter 1 22 Claremon DA, Baldwin J
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Chapter 1 56 Carini DJ, Chiu AT, Du
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Chapter 2 Chapter 2 Hybrid molecule
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identical twin drug (A-A) - 2A non-
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Chapter 2 Dimeric 1,4-dihydropyridi
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Chapter 2 plasma-protein binding si
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Chapter 2 PAF antagonist, showing o
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Corsano et al. 18 Chapter 2 have sy
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Chapter 2 Görlitzer et al. 21 synt
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Chapter 2 enzyme cyclooxygenase is
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Chapter 2 Table 4: TxA 2/PGH 2 bind
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Chapter 2 the compound had poor ora
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Chapter 2 presented to explain why
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Chapter! When two antihypertensive
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Chapter 2 Table 9: p-Receptor affin
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Chapter 2 dual vasodilating mechani
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Figure 33: Hybrid molecule DG20 (R
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5.4 Antihypertensive hybrid molecul
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Chapter 2 However, due to the terat
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Figure 43: Hybrid molecule possessi
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Chapter 2 5.4.e Hybrid molecules co
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Chapter 2 The two pairs of enantiom
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I H CH 3 Figure 50: Urapidil, an 04
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Chapter 2 15 Pilar Ortega M, Del Ca
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Chapter 2 AI Morgan TK Jr, Lis R, L
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Chapter 2 68 Baldwin JJ, Lurama WC
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Chapter 3 '2 Chapter 3 Organic nitr
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Chapter 3 phosphorylation of contra
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Chapter 3 In table 1, the in vitro
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Figure 8: Ligands for the histamine
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Chapter 3 Nitrate esters can be obt
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Chapter 3 resulting in the loss of
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Chapter 3 14 Yeates RA, Possible me
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Chapter 4 Chapter 4 2 + L-type volt
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Chapter 4 homologous domains surrou
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Chapter 4 channel, which is suggest
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Chapter 4 channel blocking activity
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Chapter 4 Structural modifications
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Chapter 4 Table 6: Calcium channel
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RiOOC COORo compound R\ R 2 nicardi
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Chapter 4 enantiomer.(-)-S11568 inh
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Chapter 4 The cardiovascular activi
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Chapter 4 rat tail artery 73 . Also
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Chapter 4 The compound HOE 166 18 (
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Figure 11: Molecular structure of a
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Chapter 4 SM-6586 was a more potent
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Chapter 4 inactivated (resting) sta
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Chapter 4 20 van Amsterdam F.T.M, Z
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Chapter 4 45 Muto K, Kuroda T, Kawa
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Chapter 4 67 Gaviraghi G, Lacidipin
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Page 159 and 160: Chapter 6 4 Results and discussion
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Page 207 and 208: Chapter 8 Based on the observations
Page 209 and 210: Chapter 8 iH-NMR (CDCI3): 1.28-1.50
Page 211 and 212: Chapter 8 13 Vitali T, Impicciatore
Page 213 and 214: Summary The investigations describe
Page 215 and 216: Samenvatting Het in dit proefschrif
Page 217 and 218: substituenten, zoals een difenylalk
Page 219 and 220: Curriculum Vitae Johannes Antonius
Page 221: voor de prettige sociale contacten
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