Bioorganic & Medicinal Chemistry Letters
Identification of the 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]
pyrimidine derivatives as highly selective PDE4B inhibitors
b
a
a
a
a
Taiji Goto a,d, , Akiko Shiina , Takeshi Murata , Masato Tomii , Takanori Yamazaki , Ken-ichi Yoshida ,
Toshiharu Yoshino a, Osamu Suzuki a, Yoshitaka Sogawa a, Kiyoshi Mizukami c, Nana Takagi a,
Tomomi Yoshitomi a, Maki Etori a, Hiroshi Tsuchida a, Tsuyoshi Mikkaichi a, Naoki Nakao a,
Mizuki Takahashi a, Hisashi Takahashi a, Shigeki Sasaki d
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a R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
b Quality & Safety Management Division, Daiichi Sankyo Co., Ltd, 3-5-1 Nihonbashihoncho, Chuo-ku, Tokyo 103-8426, Japan
c Corporate Strategy Division, Daiichi Sankyo Co., Ltd, 3-5-1 Nihonbashihoncho, Chuo-ku, Tokyo 103-8426, Japan
d Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A PDE4B subtype selective inhibitor is expected to have a wider therapeutic window than non-selective
PDE4 inhibitors. In this Letter, two series of 7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives and
5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives were evaluated for their PDE4B sub-
type selectivity using human PDE4B2 and PDE4D2 full length enzymes. To improve their PDE4B selectiv-
ity over PDE4D, we optimized the substituents on the pyrimidine ring and the side chain phenyl ring,
resulting in several derivatives with more than 100-fold selectivity for PDE4B. Consequently, we identi-
fied 2-(3-chloro-4-methoxy-phenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative
54 as a highly selective PDE4B inhibitor, which had potent hPDE4B inhibitory activity with an IC50 value
of 3.0 nM and 433-fold PDE4B selectivity over PDE4D.
Received 10 September 2013
Revised 10 December 2013
Accepted 19 December 2013
Available online 25 December 2013
Keywords:
PDE4
PDE4B
PDE4D
Ó 2014 Elsevier Ltd. All rights reserved.
Selective inhibitor
Full length
COPD
Phosphodiesterase 4 (PDE4) is expressed in inflammatory and
immune cells and mediates a hydrolysis of cyclic adenosine mono-
phosphate (cAMP).1 Since an up-regulation of cAMP contributes to
a suppression of inflammatory responses, PDE4 has been estab-
lished as an attractive target for the treatment of inflammatory dis-
eases such as asthma, chronic obstructive pulmonary disease
(COPD), and so on.2 Since the 1980s, PDE4 inhibitors with a wide
variety of chemotypes have been developed as anti-inflammatory
agents, and Roflumilast3, a second generation PDE4 inhibitor, has
been approved for the treatment of severe COPD. Indeed, Roflumi-
last and the other PDE4 inhibitors demonstrated moderate efficacy
in COPD in the clinical studies, however, the maximum dose was
limited by the mechanism-associated side effects such as nausea,
emesis, and diarrhea.
evokes a desired anti-inflammatory effect.6 Consequently, a PDE4B
selective inhibitor is expected to have a wider therapeutic window
than non-selective PDE4 inhibitors, and several attempts to obtain
a selective PDE4B inhibitor have been reported.7 However, to our
knowledge, there are no compounds advancing into clinical study
as a selective PDE4B inhibitor.
Our challenge to acquire PDE4B selective inhibitors started with
a series of fused bicyclic sulfone derivatives that we previously
reported as novel PDE4 inhibitors.8 We initially evaluated the
selectivity for PDE4B over PDE4D of our representative compounds
(Fig. 1). Compound 1 exhibited good in vitro PDE4B inhibitory
activity (IC50 = 25 nM) and high selectivity (112 folds) over PDE4D
for recombinant human PDE4B (152–564) and PDE4D (78–508).
However, when full length human PDE4B2 and PDE4D2 were used
PDE4 isozymes are coded by four distinct genes to give four iso-
forms (PDE4A-D), and 22 splice variants of these four isoforms are
known.4 In the knockout studies, it is implied that PDE4D inhibi-
tion promotes undesired adverse effects5 and PDE4B inhibition
for the assay, the PDE4B inhibitory activity of 1 decreased
(IC50 = 150 nM) and the PDE4B selectivity dropped to 3.7 folds.
Similarly, sulfide 2 and amide 3 showed only moderate PDE4B
inhibition and low selectivity for the full length enzymes.
It is known that PDE4 enzymes contain unique regulatory do-
mains, called upstream conserved regions 1 and 2 (UCR1 and
UCR2), and the UCR2 or C-terminal regulatory domain can interact
with the catalytic domain of PDE4 enzymes to regulate enzyme
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Corresponding author at: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58
Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
0960-894X/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.