Bioorganic & Medicinal Chemistry Letters
Discovery of DS79182026: A potent orally active hepcidin production
inhibitor
b
c
d
d
d
Takeshi Fukuda a, , Riki Goto , Toshihiro Kiho , Kenjiro Ueda , Sumie Muramatsu , Masami Hashimoto ,
⇑
Anri Aki b, Kengo Watanabe e, Naoki Tanaka a
a Rare Disease & LCM Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
b Biologics & Immuno-Oncology Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
c Modality Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
d Pain & Neuroscience Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
e Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. Inhibition of hep-
cidin could be a strategy favorable to treating anemia of chronic disease (ACD). We report herein the syn-
thesis and structure-activity relationships (SARs) of a series of benzisoxazole compounds as orally active
hepcidin production inhibitors. The optimization study of multi kinase inhibitor 1 led to a potent and
bioavailable hepcidin production inhibitor 38 (DS79182026), which showed serum hepcidin lowering
effects in a mouse IL-6 induced acute inflammatory model.
Received 19 April 2017
Revised 27 June 2017
Accepted 1 July 2017
Available online xxxx
Keywords:
Hepcidin
Ó 2017 Elsevier Ltd. All rights reserved.
Anemia of chronic disease
Benzisoxazole
Pyrazole
Kinase
Hepcidin is a peptide hormone, and is known as the master reg-
ulator for systemic iron mobilization.1 The maintenance of serum
iron level is important since a high iron concentration induces
oxidative organ damage, and a low iron concentration results in
iron deficiency anemia.2 As hepcidin was originally discovered as
an antibacterial peptide,3 this hormone is inducible by inflamma-
tory cytokines such as IL-6,4 in addition to iron signaling.
at the enhancement of bioavailability and lowering of the multi
kinase inhibitory activity of 1 to discover methyl {6-[5-methyl-3-
(pyridin-2-yl)-1H-pyrazol-4-yl]-1,2-benzisoxazol-3-yl}carbamate
(DS79182026, 38), a potent orally available hepcidin production
inhibitor.
As previously reported,6 we identified the indazole derivative 1
as a potent active lead compound (IC50 = 0.13 l
M).7 Although com-
Anemia of chronic disease (ACD), which includes anemia of
inflammation, is a heterogenic anemic condition due to chronic
inflammation from a basic disease, such as rheumatoid arthritis.5
Some ACD patients are known to present iron deficiency despite
abundant body iron store (termed functional iron deficiency).
Recently, high hepcidin induction based on inflammatory status
was recognized as the cause of functional iron deficiency. Hepcidin
pound 1 showed hepcidin lowering effect in mice by the intraperi-
toneal administration, pharmacokinetic (PK) profiles supported a
lack of exposure to blood in the oral administration (Table 1).
The indispensable para-hydroxyphenyl group also might be
responsible for this low exposure because of the O-glucuronidation
via UDP-glucuronosyltransferase (UGT). As an entirely fresh start,
we started to explore the alternatives of the para-hydroxyphenyl
group.
expression deficiency is
a common phenotype of hereditary
hemochromatosis. The controlling of hepcidin level would be a
promising therapeutic strategy for treating hepcidin caused func-
tional iron deficiency. Indeed, a few such biologics (e.g. NOX-
H94, LY2928057 and LY2787106) are entering clinical trials for
treatment of anemia. Herein we describe the derivatization aimed
First, we examined the bicyclic phenolic bioisosteres. The bicyc-
lic mimetics were designed to address the phenolic H-bond donor
based on the localization afforded by the complementary fused
heterocyclic rings.8 However, the benzimidazole 3, pyrolopyridine
4 and oxindole 5 were found to be surprisingly poor mimetics.
Then, we investigated the monocyclic heteroaromatics. The
transformations to pyrrole
group deteriorated hepcidin inhibitory activity. However,
the dimethylisoxazole 8 showed moderate inhibitory activity.
6 drastically lost and 4-pyridyl
⇑
7
Corresponding author.
0960-894X/Ó 2017 Elsevier Ltd. All rights reserved.