Synthesis of 4-alkyl (aryl)-6-aryl-3-cyano-2(1H)-pyridinones and their 2-imino isosteres as nonsteroidal cardiotonic agents

Article abstract of DOI:10.1016/S0014-827X(99)00004-X

Thirty new 1,2-dihydropyridine derivatives of the general formula 4-alkyl (aryl)-6-aryl-3-cyano-2(1H)-pyridinones (1-15) and 4-alkyl (aryl)-6-aryl-3-cyano-2(1H)-iminopyridines (16-30) were synthesized using one-pot multicomponent reactions of the properly substituted acetophenone, appropriate aldehyde, ammonium acetate and ethyl cyanoacetate (1-15) or malononitrile (16-30) in ethanol. These target compounds (1-30) were evaluated for their cardiotonic activity using the spontaneously beating atria model, from reserpine-treated guinea pigs. The best pharmacological profile was obtained with 3-cyano-6-(3,4-dimethoxyphenyl)-4-(4-hydroxyphenyl)-2(1H)-pyridinone (9) which displayed selectivity for increasing the force of contraction (108.7 ± 6.7,% change over control) rather than the frequency rate (40.8 ± 5.3,% change over control) at a 5 x 10^-4 M concentration. The effects of structural changes upon activity are reported.

Full text of DOI:10.1016/S0014-827X(99)00004-X

Il Farmaco 54 (1999) 195–201
Synthesis of 4-alkyl (aryl)-6-aryl-3-cyano-2(1H)-pyridinones and
their 2-imino isosteres as nonsteroidal cardiotonic agents
Ashraf Abadi a,*, Omar Al-Deeb a, Ahmed Al-Afify a, Hassan El-Kashef b
a Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud Uni6ersity, PO Box 2457, Riyadh 11451, Saudi Arabia
b Department of Pharmacology, College of Pharmacy, King Saud Uni6ersity, PO Box 2457, Riyadh 11451, Saudi Arabia
Received 2 July 1998; accepted 10 January 1999
Abstract
Thirty new 1,2-dihydropyridine derivatives of the general formula 4-alkyl (aryl)-6-aryl-3-cyano-2(1H)-pyridinones (1–15) and
4-alkyl (aryl)-6-aryl-3-cyano-2(1H)-iminopyridines (16–30) were synthesized using one-pot multicomponent reactions of the
properly substituted acetophenone, appropriate aldehyde, ammonium acetate and ethyl cyanoacetate (1–15) or malononitrile
(16–30) in ethanol. These target compounds (1–30) were evaluated for their cardiotonic activity using the spontaneously beating
atria model, from reserpine-treated guinea pigs. The best pharmacological profile was obtained with 3-cyano-6-(3,4-
dimethoxyphenyl)-4-(4-hydroxyphenyl)-2(1H)-pyridinone (9) which displayed selectivity for increasing the force of contraction
(108.796.7,% change over control) rather than the frequency rate (40.895.3,% change over control) at a 5×10−4
M
concentration. The effects of structural changes upon activity are reported. © 1999 Elsevier Science S.A. All rights reserved.
Keywords: Cardiotonics; Milrinone analogues; 2(1H)-Pyridinones
1. Introduction
Amrinone was the progenitor of this new class of
cardiotonics [6], milrinone is an analogue of amrinone
and was reported to be 50 times as active as amrinone
and to possess reduced propensity to side effects
[14,15]. Structure–activity studies indicated that it is the
methyl substituent rather than the amine–nitrile sub-
stituent interchange that is responsible for this differ-
ence in the inotorpic activities of amrinone and
milrinone [14]. However, the milrinone analogue with a
phenyl substituent instead of the methyl was found to
be inactive [16]. Also, the 3-benzoyl-2-phenyl-6-(1H)-
pyridinone derivative gave a negative inotropic effect
[17]; this was attributed to unfavorable interaction of
their side chain at C-2 with steric boundaries at the
receptor site [16,17].
Dorigo et al. [9] reported compound D (Fig. 1) as a
milrinone analogue that is more potent than milrinone
as a positive inotropic agent and with weak influence
on the frequency rate in isolated guinea pig atria. These
findings resulted in a new insight in the SAR of milri-
none analogues. Briefly, the presence of a second
pyridine nitrogen is not essential for activity, and the
replacement of the C-3 cyano by the more lipophilic
acetyl function may counteract or even exceed the
Cardiac glycosides (digoxin and digitoxin), discov-
ered in the 18th century, still represent the corner stone
of therapy of congestive heart failure (CHF), despite
their low therapeutic index and their propensity to
cause life-threatening arrhythmia [1–3]. The newer
sympathomimetic agents (dobutamine, dopamine) are
orally inactive and may lead to tachyphylaxis due to
b-receptor down regulation [4,5]. Because of the need
for safer and orally effective drugs, a series of nongly-
cosidic, non-sympathomimetic, cardiotonic agents has
been developed. Examples include, amrinone [6] (A),
milrinone [7] (B), loprinone [8] (C) and the milrinone
analogue [9] (D) (see Fig. 1 for structures A–D). Many
of the reported cardiotonics appear to drive their in-
otropic effect from inhibiting the phosphodiesterase III
isozyme, resulting in an increase of intracellular cAMP
[10,11], increasing the myofibrillar Ca2+ sensitizing
properties [12], antagonizing the negative influence of
endogenous adenosine on the heart [9], activating the
b-adrenoreceptors [9] or by mixed mechanisms [12,13].
* Corresponding author.
0014-827X/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(99)00004-X

196
A. Abadi et al. / Il Farmaco 54 (1999) 195–201
Fig. 1.
deleterious steric effect of the phenyl substituent at C-6.
This agrees with the observation that increase in
lipophilicity of the pyridine derivative correlates with
increase in inotropic activity and with adenosine antag-
onism but not with increase in chronotropism or with
PDE III inhibition [18].
In this work, we present the synthesis, characteriza-
tion and evaluation of novel milrinone analogues in
which position 2 of the pyridine ring is either a car-
bonyl or its isostere imino group, position 4 is substi-
tuted by a methyl or an aryl substituent and position 5
is unsubstituted so as to minimize the steric influence
upon position 6 substituent.
Scheme 2.
pyridinones (1–15). The structures of 1–15 were ver-
ified by IR, H NMR, MS and elementary analyses.
1
The IR spectra of compounds 1–15 showed character-
istic absorption bands of the NH group at 3600–3200
cm−1, CꢀN at 2220–2200 cm−1 and –CꢁO at 1660–
1640 cm−1 (Table 2). The mass spectra for 1–15 re-
vealed a molecular ion peak (M+) which was also the
base peak (Table 2); this denotes the relative stability of
compounds 1–15 towards electron bombardment. The
elemental analyses and 1H NMR of all derivatives
(1–15) were basically in agreement with their proposed
structures (Table 2).
2. Chemistry
The target compounds 4-alkyl (aryl)-6-aryl-3-cyano-
2(1H)-iminopyridines (16–30) were synthesized using
the aforementioned procedure except that ethyl
cyanoacetate was replaced by malononitrile (Scheme 2).
The IR spectra of 16–30 showed characteristic absorp-
tion bands at 3600–3200 cm−1 (NH) and 2220–2200
cm−1 (CꢀN). The mass spectra of 16–30 displayed a
molecular ion peak (M+) which was also the base peak
for most of the compounds (Table 2).
From a synthetic point of view, the aforementioned
synthetic procedures are considered to be multicompo-
nent reactions (MCRs) where at least three starting
materials react together in one pot to give a product
incorporating part of all starting materials. This is in
contrast to classical multi-step reactions, where only
two starting materials react. Whenever a MCR can be
applied in chemistry, this is preferred since it is easier to
perform, gives higher yields and is less time consuming
[19]. The formation of 2-oxo- and 2-iminopyridine
derivatives was assumed to proceed via the Michael
condensation of ethyl cyanoacetate or malononitrile
with a,b-unsaturated ketone, initially formed from the
reaction of the aldehyde with acetophenone [20]. Alter-
natively, the formation of 2-iminopyridines was ex-
plained by the initial formation of the arylidene-
The preparation of compounds 1–30 was depicted in
Schemes 1 and 2. Briefly, 2,4-dimethoxyacetophenone,
3,4-dimethoxyacetophenone or 3,4-dichloroacetophe-
none was reacted with the appropriate aldehyde,
namely acetaldehyde, benzaldehyde, p-chlorobenzalde-
hyde, p-hydroxybenzaldehyde, anisaldehyde, and ethyl
cyanoacetate in the presence of ammonium acetate and
ethanol to give 4-alkyl (aryl)-6-aryl-3-cyano-2(1H)-
Scheme 1.

A. Abadi et al. / Il Farmaco 54 (1999) 195–201
197
Table 1
malononitrile from the aldehyde and malononitrile fol-
lowed by its subsequent reaction with acetophenone
[20,21].
Structural and physical data of compounds 1–30
3. Experimental
3.1. Chemistry
Melting points were determined in open capillaries
on electrothermal melting-point apparatus and are un-
corrected. IR spectra were recorded on a Perkin–Elmer
1
727B spectrometer. H NMR spectra were recorded in
DMSO-d6 on a Jeol 400 MHz instrument, chemical
shifts were recorded in l (ppm) units, relative to Me4Si
as an internal standard. Microanalytical data (C, H, N)
were performed on a Perkin–Elmer 2400 analyzer and
were within 90.4% of the theoretical values. Mass
spectra were recorded on a Shimadzu PQ-5000 gas
chromatography MS apparatus. TLC was performed
on precoated silica gel plates (60-F 254, 0.2 mm) and
UV light was used for visualization.
3.2. General procedure for the preparation of 4-alkyl
(aryl)-6-aryl-3-cyano-2(1H)-pyridinones (1–15)
A mixture of the appropriate acetophenone (0.01
mol), ethyl cyanoacetate (0.01 mol), the appropriate
aldehyde (0.01 mol) and ammonium acetate (0.08 mol)
in ethanol (50 ml) was refluxed for 6 h. The reaction
mixture was cooled and the formed precipitate was
filtered, washed successively with water, dried and crys-
tallized (Tables 1 and 2).
3.3. General procedure for the preparation of 4-alkyl
(aryl)-6-aryl-3-cyano-2-(1H)-iminopyridines (16–30)
The foregoing method was carried out except that
ethyl cyanoacetate was replaced by malononitrile (Ta-
bles 1 and 2).
4. Pharmacology
4.1. Preparation of isolated guinea-pig atria
Reserpine-treated guinea pigs (300–500 g) were killed
by a blow to the head followed by exsanguination. The
chests were opened via a mid-sternal incision, the peri-
cardium and facia around the heart were removed and
the heart was exposed. The hearts were rapidly placed
in a Petri dish filled with physiological salt solution
(PSS) and aerated with 95% O2 and 5% CO2 in which
the right atrium was separated from the rest of the
heart. The atria were then placed in 10 ml organ baths

198
A. Abadi et al. / Il Farmaco 54 (1999) 195–201
Table 2
Analytical data of compounds 1–30
Comp.
1
Analysis
IR (KBr, cm−1
)
MS m/z (%)
270 (100)
332 (100)
366 (100)
348 (100)
362 (100)
270 (100)
332 (100)
366 (100)
348 (100)
362 (100)
278 (100)
340 (100)
374 (100)
356 (100)
370 (100)
269 (100)
331 (100)
1H NMR (DMSO-d6)
C15H14N2O3
C20H16N2O3
C20H15ClN2O3
C20H16N2O4
C21H18N2O4
C15H14N2O3
C20H16N2O3
C20H15ClN2O3
C20H16N2O4
C21H18N2O4
C13H8Cl2N2O
3450–3250, 2200,
1650
3600–3300, 2200,
1660
3600–3200, 2210,
1660
3400–3200, 2220,
1660
3500–3400, 2200,
1640
3500–3350, 2210,
1660
3600–3300, 2210,
1640
3500–3200, 2210,
1660
3450–3250, 2200,
1650
3600–3350, 2210,
1660
3600–3300, 2210,
1650
3600–3300, 2210,
1660
3600–3300, 2210,
1660
3450–3200, 2220,
1660
3500–3300, 2200,
1650
3460, 3300, 2210
2.35 (s, 3H, CH3), 3.82 (s, 3H, 2-OCH3), 3.84 (s, 3H, 4-OCH3),
6.60–7.75 (m, 4H, aromatic), 12.20 (brs, 1H, NH)
3.83 (s, 6H, 2 and 4-OCH3), 6.51–7.68 (m, 9H, aromatic), 12.4
(brs, 1H, NH)
3.82 (s, 3H, 2-OCH3), 3.85 (s, 3H, 4-OCH3), 6.5–7.72
(m, 8H, aromatic), 12.20 (brs, 1H, NH)
3.82 (s, 6H, 2 and 4-OCH3), 6.45–7.58 (m, 8H, aromatic), 10.4
(s, 1H, OH), 12.4 (brs, 1H, NH)
3.83 (s, 9H, 2, 4 and 4-OCH3), 6.48–7.68 (m, 8H, aromatic),
12.20 (brs, 1H, NH)
2.39 (s, 3H, CH3), 3.81 (s, 3H, 3-OCH3), 3.84 (s, 3H, 4-OCH3),
6.75–7.39 (m, 4H, aromatic), 12.4 (brs, 1H, NH)
3.82 (s, 3H, 3-OCH3), 3.85 (s, 3H, 4-OCH3), 6.84–7.71
(m, 9H, aromatic), 12.4 (brs, 1H, NH)
3.82 (s, 3H, 3-OCH3), 3.84 (s, 3H, 4-OCH3), 6.83–7.74
(m, 8H, aromatic), 12.50 (brs, 1H, NH)
3.82 (s, 3H, 3-OCH3), 3.84 (s, 3H, 4-OCH3), 6.30–7.90
(m, 8H, aromatic), 10.02 (brs, 1H, OH), 12.20 (brs, 1H, NH)
3.82 (s, 3H, 3-OCH3), 3.84 (s, 6H, 2 and 4-OCH3), 6.80–6.75
(m, 8H, aromatic), 12.40 (brs, 1H, NH)
2.41 (s, 3H, CH3), 6.90 (s, 1H, aromatic), 7.78 (s, 2H, aromatic),
8.10 (s, 1H, aromatic), 12.25 (brs, 1H, NH)
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
C
18H10Cl2N2O
C18H9Cl3N2O
18H10Cl2N2O2
C19H12Cl2N2O2
15H15N3O2
7.05–8.25 (m, 9H, aromatic), 12.30 (brs, 1H, NH)
7.05–8.24 (m, 8H, aromatic), 12.20 (brs, 1H, NH)
C
6.92–8.21 (m, 8H, aromatic), 10.20 (brs, 1H, OH),
12.2 (brs, 1H, NH)
3.83 (s, 3H, OCH3), 6.97–8.25 (m, 8H, aromatic),
12.25 (brs, 1H, NH)HHh
2.35 (s, 3H, CH3), 3.83 (s, 6H, 2 and 4-OCH3), 6.80–8.55
(m, 9H, aromatic and NHs)
3.82 (s, 6H, 2 and 4-OCH3), 6.66–7.84 (m, 11H, aromatic and NHs)
C
C20H17N3O2
3500–3450, 3400–
3300, 2200
18
19
C20H16ClN3O2
C20H17N3O3
3460, 3320, 2200
3450, 3350–3250,
2200
365 (100)
347 (100)
3.83 (s, 6H, 2 and 4-OCH3), 6.70–7.95 (m, 10H, aromatic and NHs)
3.82 (s, 3H, 2-OCH3), 3.83 (s, 3H, 4-OCH3), 6.64–7.81
(m, 10H, aromatic and NHs), 9.93 (brs, 1H, OH)
3.81 (s, 3H, 3-OCH3), 3.83 (s, 6H, 2 and 4-OCH3), 6.66–7.82
(m, 10H, aromatic and NHs)
2.35 (s, 3H, CH3), 3.83 (s, 3H, 3-OCH3), 3.85 (s, 3H, 4-OCH3),
6.74–7.69 (m, 6H, aromatic and NHs)
3.82 (s, 3H, 3-OCH3), 3.84 (s, 3H, 4-OCH3), 6.95–7.75
(m, 11H, aromatic and NHs)
3.82 (s, 3H, 3-OCH3), 3.84 (s, 3H, 4-OCH3), 6.90–7.90
(m, 10H, aromatic and NHs)
3.80 (s, 1H, 3-OCH3), 3.83 (s, 6H, 2 and 4-OCH3),
6.87–7.73 (m, 10H, aromatic and NHs)
3.80 (s, 3H, 3-OCH3), 3.83 (s, 6H, 2 and 4-OCH3),
6.87–7.73 (m, 10H, aromatic and NHs)
20
21
22
23
24
25
C21H19N3O3
C15H15N3O2
C20H17N3O2
C20H16ClN3O2
C20H17N3O3
C21H19N3O3
3450, 3280, 2200
361 (100)
269 (100)
331 (100)
365 (100)
347 (100)
361 (100)
3450, 3260, 2200
3520–3440, 3400–
3320, 2190
3450, 3320, 2200
3460, 3360, 2200
3470, 3360, 2200
26
27
28
C13H9Cl2N3
C18H11Cl2N3
C18H10Cl3N3
3450, 3330, 2210
3450, 3350, 2200
3460, 3340, 2200
277 (100)
339 (100)
373 (20)
44 (100)
355 (55)
44 (100)
369 (100)
2.40 (s, 3H, CH3), 6.83–7.87 (m, 6H, aromatic and NHs)
6.85–7.94 (m, 11H, aromatic and NHs)
6.85–8.55 (m, 10H, aromatic and NHs)
29
30
C18H11Cl2N3O
C19H13Cl2N3O
3470, 3350, 2200
3470, 3330, 2200
6.90–8.50 (m, 10H, aromatic and NHs), 10.0 (brs, 1H, OH)
3.84 (s, 3H, OCH3), 7.06–8.51 (m, 10H, aromatic and NHs)
containing PSS of the following composition (in mM):
NaCl, 120; KCl, 2.7; MgCl2, 0.9; NaH2PO4, 0.4; CaCl2,
1.37; NaHCO3, 11.9 and glucose, 5.5 [9]. The solution
was maintained at 34°C and was bubbled vigorously

A. Abadi et al. / Il Farmaco 54 (1999) 195–201
199
Table 3
Effect of compounds 1–30 upon contractile activity and frequency rate of spontaneously beating atria from reserpine-treated guinea pigs at
5×10−4 M concentration
Comp.
Developed tension
Frequency rate
Comp.
Developed tension
Frequency rate
(% change overcontrol) a
(% change over control) a
(% change overcontrol) a
(% change over control) a
b
b
b
b
b
b
b
b
b
b
b
b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
46.194.3
4295.7
11.992.1
4.690.2
2593.4
28.794.1
37.692.7
34.494.1
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
21.190.9
3593.1
108.796.7
40.896.7
b
b
b
b
b
b
b
b
19.391.5
31.791.4
b
b
b
b
b
18.391.1
15.293.6
b
b
14.291.0
Isoproterenol
sulphate
83.794.1
76.493.8
a Mean9SEM from four atria.
b No inotropic or chronotropic effect.
with a mixture of 95% O2 and 5% CO2 which produced
pH 7.5. The resting tension was adjusted at 1 g and
developed tension was recorded isometrically by means
of a Myograph F-60, Narco Bio-System isometric
transducer. Signals from the force transducer were con-
tinuously recorded on a Narco Bio-System, MK-111
physiograph. After a period of stabilization of 60 min,
control measurements of contractile force and fre-
quency were made.
Data are presented as the mean9SEM (Table 3),
statistical comparisons were made by Student’s t-test
for paired data. Significance was accepted at P=0.05
[22]. The results are shown in Table 3.
4.3. Acute toxicity
Four groups of mice, each consisting of six animals,
were used. The compounds were given orally in doses
of 1, 10, 100 and 500 mg/kg, respectively. Twenty-four
hours later, the % mortality in each group and for each
compound was recorded and the LD50 was calculated
using the method described by Litchfield and Wilcoxon
[23].
4.2. Effect on isolated atria
The experiments were performed on spontaneously
beating atria obtained from reserpine-treated guinea
pigs. Reserpine (2 mg/kg, i.p.) was given 24 h before the
animals were sacrificed in order to eliminate the influ-
ence of noradrenaline, which might be released from
the sympathetic nerve terminals. Noradrenaline deple-
tion was determined by exposing the isolated atria to a
single dose of tyramine (2 mg/ml) before starting the
experiments. Experiments were performed only in
preparations not responding to tyramine. All com-
pounds were added to the perfusion fluid in a final
concentration of 5×10−4 M. After each addition, the
inotropic effect was recorded for 3 min before washing
and replacement of the perfusion fluid [9,17].
5. Results and discussion
Biological evaluation of compounds 1–30 as car-
diotonic agents using the spontaneously beating atria
model from reserpine-treated guinea pigs to eliminate
the influence of noradrenaline upon contractility was
adopted. Isoproterenol sulfate was used as a positive
control. Inotropic and chronotropic activities were ex-
pressed as % change in the force of contraction and
frequency rate over control (Table 3).
All compounds were dissolved in DMSO and added
to the bath in a volume of 100 ml. The same volume of
DMSO did not produce any effect. Isoproterenol sul-
fate at a concentration of 5×10−4 M was used as a
reference standard to be able to follow the changes in
both the atria contractility and frequency rate.
Replacement of the cyclic amide oxygen by an imino
group afforded a series of isosteric compounds 1–15
versus 16–30, respectively. There is no clear direction
to the effect of this oxygen-imino isosterism upon in-
otropic activity, for example 4\19; 8\23; 9\24 and
14\29; on the contrary 20\5; 27\12 and 30\15

200
A. Abadi et al. / Il Farmaco 54 (1999) 195–201
Fig. 2. Effects of compounds 20, 5, 4, and 9 (in a final concentration of 5×10−4 M) on the contractile activity of the spontaneously beating
guinea-pig atria.
hardt et al. [25], recognized four binding sites: one for a
resonance dipole moiety similar to acidic amide, a
binding site for an electron-rich center similar to a
double bond both in one plane, a binding area for p
electrons when the latter are turned approximately 20°
from the perpendicular to the plane established by the
first two sites and this site probably protrudes from the
top of the receptor pocket, and a site nearly in the
plane of the first two sites that interacts with an elec-
tron-rich system. Also, the aforementioned model rec-
ognized two steric boundaries one on each side of the
first two binding sites. In that respect, our molecules are
not compatible with Erhardt’s model; thus, mechanisms
of action other than the inhibition of PDE III cannot
be excluded.
The LD50 values of four active compounds, namely
4, 5, 9 and 20, were determined in mice and found to be
258 mg/kg for 9, while others were found to be safe up
to 500 mg/kg.
In conclusion, some of the prepared compounds were
found to possess cardiotonic activity in vitro, together
with selectivity e.g. 9, 19 and 30, and they represent a
good model for future derivatization. An investigation
into the activity of these compounds using an in vivo
model and their exact mechanism of action is currently
underway.
(Table 3). This indicates that a cyclic amide is not a
requisite for cardiotonic activity and that the NH iso-
steric group may replace the lactam oxygen without
loss of cardiotonic activity. Regarding the substituent
at C-4 of the pyridine ring, in all cases the presence of
a methyl substituent leads to inactive compounds (1, 6,
11, 16, 21 and 22, Table 3) regardless of the nature of
the other substituents. Meanwhile, the introduction of a
phenyl or p-chlorophenyl substituent to C-4 of the
pyridine ring led to inactive compounds in most cases
e.g. 2, 3, 7, 12, 13, 17, 18, 22, 23 and 28. The two
exceptions were compounds 8 and 27; even with the
cardiotonic activity of the latter, their effect on the
frequency rate exceeded their effect on the force of
contraction (approximately 1.6 times in both cases,
Table 3). On the other hand, substitution of the
pyridine 4 position by p-hydroxyphenyl or p-methoxy-
phenyl groups, that are eventually able to form hydro-
gen bonding produced active cardiotonics as in the case
of 4, 5, 9, 14, 19, 20 and 30 (Fig. 2) and their car-
diotonic effect was accompanied by either no, lower or
equal effect upon frequency rate (Table 3).
The obtained data clearly indicate the obvious neces-
sity for an aromatic substituent in position 4 of the
pyridine ring for cardiotonic activity and the modulat-
ing influence of this substituent upon selectivity (in-
otropy versus chronotropy). In addition, it should be
taken into consideration that substitution of the
pyridine ring in position 4 rather than position 5 re-
duces the additive steric effect that the position 5
substituent may have upon the fitting of position 6
substituent into its receptor. Comparing the activities of
the synthesized compounds relative to the electronic,
lipophilic and steric parameters of the C-4 aryl sub-
stituent [24] signifies the relevance of the electronic
properties of this substituent to inotropic activity rather
than the lipophilic or steric ones (compounds 4, 5, 9
and 20 were the most active of the series). For the
pyridine C-6 substituent, it appears that the presence of
an aryl substituent at this position, particularly with the
absence of C-5 substitution, does not cause loss of
cardiotonic activity. The topological model for cardiac
cAMP phosphodiesterase receptors, developed by Er-
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