Synthesis and biological activities of 1-pyridylisoquinoline and 1-pyridyldihydroisoquinoline derivatives as PDE4 inhibitors

Article abstract of DOI:10.1016/S0960-894X(03)00438-4

A novel series of 1-pyridylisoquinoline and 1-pyridyldihydroisoquinoline derivatives has been prepared. These compounds showed potent PDE4 inhibitory activities and a broad margin between the K_i value of the rolipram binding affinity and the IC₅₀ value of PDE4 inhibition. They also exhibited potent inhibitory activities toward LPS-induced TNF-α production in mice.

Full text of DOI:10.1016/S0960-894X(03)00438-4

Bioorganic& Medicinal Chemistry Letters 13 (2003) 2347–2350
Synthesis and Biological Activities of 1-Pyridylisoquinoline and
1-Pyridyldihydroisoquinoline Derivatives as PDE4 Inhibitors
Tatsuzo Ukita,a,* Masakatsu Sugahara,a Yoshihiro Terakawa,a Tooru Kuroda,a
Kazuteru Wada,a Aya Nakata,b Hideo Kikkawa,b Katsuo Ikezawab and Kazuaki Naitob
aDiscovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 3-16-89, Kashima, Yodogawa, Osaka 532-8505, Japan
bDiscovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 2-2-50, Kawagishi, Toda, Saitama 335-8505, Japan
Received 24 January 2003; accepted 19 April 2003
Abstract—A novel series of 1-pyridylisoquinoline and 1-pyridyldihydroisoquinoline derivatives has been prepared. These com-
pounds showed potent PDE4 inhibitory activities and a broad margin between the Ki value of the rolipram binding affinity and the
IC50 value of PDE4 inhibition. They also exhibited potent inhibitory activities toward LPS-induced TNF-a production in mice.
# 2003 Elsevier Science Ltd. All rights reserved.
Cyclic nucleotide phosphodiesterases (PDEs) play a key
role in the metabolism of purine cyclic nucleotides,
cAMP and cGMP. PDEs have been classified into ele-
ven structurally, biochemically, and pharmacologically
distinct families.1 Among them, cAMP-PDE (PDE4),
consisting of four gene products (PDE4A to PDE4D), is
characterized by selective, high-affinity hydrolysis of
cAMP.2 The inhibition of PDE4 results in the increase
in cellular levels of cAMP, which contributes to both
the relaxation of airway smooth muscle and the pre-
vention of proinflammatory cell activation.3 In parti-
cular, this type of manipulation brings about a marked
reduction in the release of the proinflammatory cytokine
TNF-a into the blood.4 These observations have gener-
ated considerable interest in the use of PDE4 inhibitors
for the treatment of various immunological disorders,
including asthma, COPD (chronic obstructive pulmon-
ary disease), and rheumatoid arthritis.5
oral in vivo activities by the introduction of an addi-
tional heteroatom to the naphthalene ring of 1-pyr-
idylnaphthalene
derivatives,
we
now
disclose
1-pyridylisoquinoline and 1-pyridyldihydroisoquinoline
derivatives having potent PDE4 inhibitory activities and
a broad margin between the Ki value of the rolipram
binding affinity and the IC50 value of PDE4 inhibition.
They also exhibited potent inhibitory activities toward
lipopolysaccaride (LPS)-induced TNF-a production in
mice.
Chemistry
In order to introduce an additional heteroatom to the
naphthalene ring of 1-pyridylnaphthalene derivatives,
we designed compounds 4, 5a, and 6a, which were ana-
logues of compound 3a and 3b, as shown in Scheme 1.
In terms of a dihydroisoquinoline scaffold, we selected
the S-stereoisomer, because it was reported that SDZ
With a considerable amount of interest and excitement,
the novel structural classes of PDE4 inhibitors such as
benzofuran, benzodiazepine, naphthyridine, etc. have
recently been reported as second generation inhibitors.6
We have already reported 1-pyridylnaphthalene deriva-
tives as a new structural class of selective PDE4 inhibi-
tors.7 In connection with our efforts in search of a new
scaffold to improve pharmacokinetic properties and
*Corresponding author. Tel.: +81-6-6300-2566; fax: +81-6-6300-
2564; e-mail: t-ukita@tanabe.co.jp
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00438-4

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T. Ukita et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2347–2350
(D-ring) was introduced, and (4) the pyridyl group (C-
ring) was fixed from the previous SAR study.7
Quinoline derivative 4 was prepared in five steps from
4-aminoveratrole 7 (Scheme 2). 1-Pyridylquinoline inter-
mediate 9 was synthesized by the Friedel-Crafts acyl-
ation of 7 with 2-chloro-4-cyanopyridine, followed by
acid catalyzed cyclization of 8 with tetronicacid. Lac-
tone 9 was converted to alcohol 10 by reduction with
Red-Al1. Quinoline derivative 4 was synthesized by the
reaction of chloride 10 with hydrazine hydrate, followed
by cyclization with 2-(3-pyridinoyl)benzoic acid.
Isoquinoline derivatives 5a–c were prepared in five steps
from bromo acetal 129 (Scheme 3). Benzaldehyde 13
was synthesized by nucleophilic addition of lithium salt
of 12 to 2-chloro-N,N-dimethylisonicotinamide, fol-
lowed by deprotection of acetal in acidic media. 1-Pyr-
idylisoquinoline intermediate 14 was obtained by
cyclization of 13 with methyl isocyanoacetate and NaH.
Isoquinoline derivatives 5a–c were synthesized by
reduction of ester 14 with Red-Al1, followed succes-
sively by the reaction with hydrazine hydrate and by
cyclization with 2-(heteroarylcarbonyl)benzoic acid.
Dihydroisoquinoline derivatives 6a–e were prepared in
six steps from l-DOPA derivative 1710 (Scheme 4).
Compound 19 was synthesized by the condensation of
17 with 2-bromo-isonicotinic acid, followed by reduc-
tion of ester 18 with NaBH4–MeOH.11 Phthalazinone
or isoquinolone moiety was introduced into 19 to give
compounds 20a–e by the Ullmann condensation in the
presence of a catalytic amount of CuI.12 Dihy-
droisoquinoline derivatives 6a–e were synthesized by
Scheme 1.
ISQ 844 was a PDE3/4 dual inhibitor and its S-stereo-
isomer was more potent than R-stereoisomer.8 In this
approach, (1) the naphthalene part (A,B-ring) was
transformed to a quinoline, isoquinoline, or dihydro-
isoquinoline part, (2) 3-hydroxymethyl group was kept,
(3) the heterocyclic compound having a carbonyl group
Scheme 2. Reagents and conditions: (a) 2-chloro-4-cyanopyridine,
BCl3/ClCH2CH2Cl, refluxꢀ: (b) tetronic acid, TFA/toluene-AcOH,
pyridinoyl)benzoic acid/ethylene glycol, 150 ꢀC, (2) 2N aqueous HCl/
CHCl3–MeOH.
Scheme 3. Reagents and conditions: (a) (1) n-BuLi, 2-chloro-N,N-
dimethylisonicotinamide/THF, À70 ꢀC, (2) concd HClaq; (b) methyl
isocyanoacetate, NaH/DMF, 50 ꢀC; (c) Red-Al/THF, 0 ꢀC; (d)
NH2NH2 H2O, reflux; (e) (1) 2-(heteroarylcarbonyl)benzoic acid/eth-
ylene glycol, 150 ꢀC, (2) 2N aqueous HCl/CHCl3–MeOH.
.
reflux; (c) Red-Al/THF, 0 C; (d) NH2NH2 H2O, reflux: (e) (1) 2-(3-
.

T. Ukita et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2347–2350
2349
acetylation of hydroxy group of compounds 20a–e, fol-
lowed successively by the Bischler-Napieralski cycli-
zation of compounds 21a–e with POCl3 and by
deprotection of acetyl group with aqueous LiOH.
compounds 5b, c, and 6b–e exhibited almost the same
activities (IC50=0.3–3 nM) as 3a and b. The affinities
for the high-affinity rolipram binding site were also
investigated. All compounds 5a–c and 6a–e exhibited
comparatively lower affinities than 2 for the high affinity
rolipram binding site (Ki value (nM); 5a–c and 6a–e:
1.4–6.5, 2: 0.85). In particular, compounds 5b, 5c, 6a,
6d, and 6e showed broader margin between the Ki value
of the rolipram binding affinity and the IC50 value of
PDE4 inhibition (ratio 0.15–0.28, respectively) than 2
(ratio 0.35).
Table 1. PDE4 Inhibitory activities and rolipram binding affinity
Compd
PDE4 inhibition,
IC50, nMa, (A)
[3H]-Rolipram
binding,
Ki, nMa, (B)
Ratio
A/B
1 (Rolipram)
2 (RP 73401)
3a
3b
4
5a
5b
5c
6a
6b
6c
6d
6e
500
0.3
0.7
0.7
70
0.6
0.3
0.3
1
3
2
0.4
0.5
3.8
0.85
3.5
132
0.35
0.20
0.23
0.58
0.43
0.18
0.21
0.15
0.56
0.65
0.27
0.28
3.0
120
1.4
1.7
1.4
6.5
5.4
3.1
1.5
1.8
aIC50 and Ki values were determined from the logarithmic concen-
tration–inhibition curve (at least four points). The value is given as the
mean of three experiments, where the variation from the mean value is
20% or less.
Next we selected five compounds on the basis of PDE4
inhibitory potency (IC50<1 nM) and broad margin
(ratio<0.35) between the Ki value of the rolipram
binding affinity and the IC50 value of PDE4 inhibition,
for further evaluation of their ability to inhibit LPS-
induced TNF-a production in mice, as shown in Table 2.
Compounds 5b, 6a, and 6e proved to be more potent
than 2 (5b, ED50=0.26 mg/kg; 6a, ED50=0.52 mg/kg;
6e, ED50=0.13 mg/kg; 2, ED50=0.72 mg/kg). On the
other hand, 5c and 6d led to a decrease in potency (5c,
ED50=1.6 mg/kg; 6d, ED50=2.4 mg/kg). For example,
5c exhibited lower inhibition of LPS-induced TNF-a
production than 5b in spite of the same potencies for
PDE4 inhibition (5b, IC50=0.3 nM; 5c, IC50=0.3 nM),
in 1-pyridylisoquinoline derivatives. Furthermore, 6d
also exhibited lower inhibition of LPS-induced TNF-a
Scheme 4. Reagents and conditions: (a) DCC, HOBt, 2-bromo-iso-
nicotinic acid/CH2Cl2, 25 ꢀC; (b) NaBH4/THF-MeOH, reflux; (c) RH,
CuI, K2CO3/DMF, 120 ꢀC; (d) Ac2O, Et3N/CH2Cl2, 25 ꢀC; (e) POCl3/
CH3CN, reflux; (f) (1) LiOH H2O/MeOH, 25 C, (2) 2N aqueous HCl/
CHCl3–MeOH.
ꢀ
.
Biological Results and Discussion
The IC50 value of PDE4 inhibition, the Ki value of
binding affinity for the rolipram binding site, and the
ratio of both values are summarized in Table 1. Trans-
formation of the naphthalene part to quinoline, iso-
quinoline, or dihydroisoquinoline part was first
examined. Quinoline derivative 4 proved to have a
rather weak PDE4 inhibitory activity despite its struc-
tural resemblance to 3a (4, IC50=70 nM; 3a, IC50=0.7
nM). On the other hand, isoquinoline 5a and dihy-
droisoquinoline derivative 6a exhibited almost the same
activities as 3a and 3b (5a, IC50=0.6 nM; 6a, IC50=1.0
nM; 3b, IC50=0.7 nM). Next we paid attention to the
transformation of the D-ring to further increase the
PDE4 inhibitory activity. Among their compounds,
Table 2. Inhibition of LPS-induced TNF-a production
Compd
TNF-a, ED50, mg/kg, poa
1 (Rolipram)
2 (RP 73401)
2.6
0.72
1.2
0.26
1.6
0.52
2.4
3a
5b
5c
6a
6d
6e
0.13
aED50 values were determined from dose-response curves of TNF-a
inhibition. Compounds were administered orally to mice 30min prior
to LPS challenge.

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T. Ukita et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2347–2350
production than 6a and 6e in spite of almost the same
potencies for PDE4 inhibition (6a, IC50=1.0 nM; 6d,
IC50=0.4 nM; 6e, IC50=0.5 nM), in 1-pyridyldihy-
droisoquinoline derivatives. More lipophilicderivatives
5c and 6d showed less potencies than 5b, 6a, and 6e in
this assay [calculated log D at pH 6.5: 5c; 3.47 vs 5b;
2.38 (1-pyridylisoquinoline derivatives): 6d; 1.94 vs 6a;
1.26, 6e; 1.40 (1-pyridyldihydroisoquinoline deriva-
tives)]. These findings might be ascribed to the differ-
ences of physicochemical properties (cell permeability,
water solubility) among these compounds.
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In conclusion, 1-pyridylisoquinoline and 1-pyridyldihy-
droisoquinoline derivatives were disclosed as novel
structural classes of PDE4 inhibitors with improved oral
in vivo activities. Among these analogues, compounds
5b, 6a, and 6e were found to be potent inhibitors against
both the inhibitory activities of PDE4 and LPS-induced
TNF-a production, and also showed a broad margin
between the Ki value of the rolipram binding affinity and
the IC50 value of PDE4 inhibition. Further studies on
this interesting class of PDE4 inhibitors are in progress.
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