Bioorganic & Medicinal Chemistry Letters
The discovery of avanafil for the treatment of erectile dysfunction: A
novel pyrimidine-5-carboxamide derivative as a potent and highly
selective phosphodiesterase 5 inhibitor
Toshiaki Sakamoto a, Yuichi Koga a, Masataka Hikota a, Kenji Matsuki a, Michino Murakami b,
Kohei Kikkawa b, Kotomi Fujishige c, Jun Kotera c, Kenji Omori c,d, Hiroshi Morimoto a, , Koichiro Yamada a
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a Medicinal Chemistry Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan
b Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan
c Advanced Medical Research Laboratories, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan
d Industry and Academia Cooperation Research Project, Laboratory of Target and Drug Discovery, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho,
Chikusa-ku, Nagoya 464-8601, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel pyrimidine-5-carboxamide derivatives bearing a 3-chloro-4-methoxybenzylamino group at the
4-position were identified as potent and highly selective phosphodiesterase 5 inhibitors. Among them,
we successfully found 10j (avanafil) which exhibited a potent relaxant effect on isolated rabbit cavernosum
(EC30 = 2.1 nM) and a high isozyme selectivity.
Received 4 September 2014
Revised 30 September 2014
Accepted 2 October 2014
Available online 28 October 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
PDE5
PDE6
Erectile dysfunction
Avanafil
Several orally available phosphodiesterase 5 (PDE5) inhibitors
have been developed and are prescribed as first-line therapy for
the treatment of erectile dysfunction (ED).1 Since PDEs consist of
a superfamily with 11 subfamilies (PDE1–11) and each of them
plays important roles in various tissues,2 it is necessary to develop
a PDE5 selective inhibitor in order to avoid adverse effects result-
ing from inhibition of the other PDEs. For example, the first
launched orally active PDE5 inhibitor, sildenafil showed high
efficacy, but visual side effects such as cyanopsia and visual distur-
bance were reported in some cases.3,4 These adverse effects are
indicated to be attributed to inhibition of PDE6, which is expressed
in photoreceptor cells of the retina and plays important roles for
the photo signal transmission.5
In a previous paper, we reported findings of 5-(3,4,5-trim-
ethoxybenzoyl)-4-amimopyrimidine derivatives as a novel chemi-
cal class of highly selective PDE5 inhibitors by scaffold hopping
from isoquinoline derivatives (Fig. 1).6 Although T-6932 (1) showed
a potent PDE5 inhibitory activity and an improved selectivity over
PDE6, its relaxant effect on isolated rabbit corpus cavernosum
was moderate (EC30 = 53 nM) owing to its high lipophilicity
(cLogP = 4.58). Therefore, the substituents at the 2- and 5-positions
of the pyrimidine ring were explored to potentiate the relaxant
effect while maintaining a high PDE5 selectivity against PDE6. In
this paper, we report the discovery of the novel, potent, and highly
selective PDE5 inhibitor avanafil 10j. The details of synthesis and
structure–activity relationships are described.
Aiming to improve its high lipophilicity of T-6932, pyrimidine-
5-carboxamide derivatives were designed. In the course of the
synthesis described in Scheme 1, the synthetic intermediate, ethyl
pyrimidine-5-carboxylate derivative 4, was found to show single
digit nanomolar activity for PDE5 (IC50 = 5.5 nM) and a slightly
improved relaxant effect (EC30 = 37 nM) compared to that of
T-6932.7 These results indicate that the 3,4,5-trimethoxybenzene
moiety, which caused the high lipophilicity of T-6932, was not cru-
cial for PDE5 inhibitory activity. Therefore, pyrimidine-5-carboxyl-
ate or carboxamide derivatives bearing more hydrophilic
substituents were designed and synthesized as in Scheme 1.
4-Aminopyrimidine derivative 3 was obtained by condensation
of commercially available 2 with 3-chloro-4-methoxybenzylamine.
After oxidation of the methylsulfanyl group with mCPBA, the
2-position of the pyrimidine ring was substituted with 2-hydroxy-
methylpyridine in the presence of sodium hydride to give 4. In this
reaction, 2-hydroxypyrimidine derivative 5 was obtained in 55%
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Corresponding author. Tel.: +81 045 963 7164; fax: +81 045 963 7165.
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.