Current Opinion in Investigational Drugs

12 Current Opinion in Investigational Drugs 2006 Vol 7 No 1
Current Opinion
A number of new approaches to the treatment of diabetes
are being pursued. Of these, the development of DPP-IV
inhibitors is by far the most advanced, with three
compounds (MK-431 (Merck & Co Inc/Banyu
Pharmaceutical Co Ltd/Ono Pharmaceutical Co Ltd),
saxagliptin (Bristol-Myers Squibb Co) and vildagliptin
(Novartis Institutes for BioMedical Research Inc)) currently
in phase III clinical trials. These compounds, like nearly all
other DPP-IV inhibitors, are based on the almost ubiquitous
2-pyrrolonitrile chemotype. Few other chemotypes have
been described, and the compounds claimed in this
application represent a considerable variation in this regard.
This difference may be due to the successful exploitation of
structure-aided drug design that is the focus of research at
Takeda San Diego (formerly Syrrx).
Oncological
Selected by Peter Norman (Norman Consulting, Burnham,
Bucks, UK)
New 6-phenylfuro[2,3-d]pyrimidine derivatives are DDR2
tyrosine kinase inhibitors - useful for the treatment of
rheumatoid arthritis, cirrhosis and cancer
KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY/JEIL
PHARMACEUTICAL CO LTD (Yang B-S, Yang K-M, Kim H-J, Park
I-S, Park S-D, Lee J-H, Kwon H-M, Woo B-Y)
WO-2005092896, 06 October 2005
Novel 6-phenylfuro[2,3-d]pyrimidine derivatives and their
salts, compositions containing them, their use as inhibitors
of the discoidin domain receptor (DDR)2 tyrosine kinase,
and in the treatment of hepatocirrhosis, rheumatism and
cancer are claimed. The DDR protein has been reported to
enhance the development of fibroblasts and to show
increased expression in metastatic cancer cells. The claimed
compounds are the first low-molecular-weight inhibitors of
DDR2 kinase described. In a rat cannulated bile duct model
of cirrhosis, administration of one compound (10
mg/kg/day for 2 weeks) inhibited hydroxy furorin
production from 4.93 to 2.23 mg/g (the normal level).
Approximately 200 compounds are exemplified. No
compounds are specifically claimed.
Cl
O
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CH3 HN
WO-2005092896
(Korea Institute of Science and Technology/Jeil)
Current Opinion
DDR2 is a widely expressed member of a subfamily of
receptor tyrosine kinases whose ligands are fibrillar
collagens. Studies in knockout mice suggest that it acts to
regulate cellular proliferation and, for example, fibroblast
signaling. Tyrosine kinases in this subfamily have attracted
little attention until now, thus the appearance of this
application claiming the first documented inhibitors of
N
S
N
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DDR2 kinase is likely to evoke considerable efforts in the
field. The claimed compounds also represent a novel
chemotype of tyrosine kinase inhibitor, which may have
enhanced selectivity compared with the better characterized
tyrosine kinases.
New thioalkeneamide derivatives are transketolase
inhibitors - useful for the treatment of cancer
ARRAY BIOPHARMA INC (Boyd SA)
WO-2005095344, 13 October 2005
Novel thioalkeneamide derivatives and their use, either
alone or in combination with a thiamine-restricted diet
and/or other therapeutic agents, to inhibit transketolase
activity and cellular nucleic acid synthesis, and to reduce the
cellular levels of ribulose/ribose-5-phosphate are claimed.
These compounds are also claimed to increase apoptosis in
tumor cells and to reduce tumor growth. They are stated to
be additionally useful as inhibitors of metastasis and
angiogenesis. No suitable advantage is given. Several
compounds are specifically claimed, including N-(2-amino-6methylpyridin-3-ylmethyl)-N-{2-[2-[(2-amino-6-methylpyridin-3ylmethyl)formylamino]-1-(2-hydroxyethyl)-propenyl-disulfanyl]-
4-hydroxy-1-methylbut-1-enyl}formamide (AR-00342632), which
had an IC50 value of 10 nM against HCT116 colon carcinoma
cells in vitro.
C
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N
NH 2
C
H 3
N
O
H
S S
OH
OH
H
WO-2005095344
(Array)
N
CH 3
O NH 2
Current Opinion
Transketolase is a metabolic enzyme that plays a crucial role
in tumor cell nucleic acid synthesis, using glucose through
the elevated non-oxidative pentose phosphate pathway.
Thus, inhibitors of this enzyme constitute a novel approach
to the treatment of cancer. To date, this possibility has been
almost completely neglected, with only Array's disclosure of
the activity of AR-00342632 at the 2005 American Chemical
Society meeting, and S*BIO and Chiron's description of the
identification of lead compounds via high-throughput
screening indicating any interest. This application was one
of two from Array (see also WO-2005095391). AVEO
Pharmaceuticals published WO-2005094803 claiming such
inhibitors on the same day.
New 2-aminomethylthiazole-5-carboxamide derivatives
are protein kinase modulators - useful for the treatment
of, eg, neurological disease and cancer
LEXICON GENETICS INC (Jin H, Shi Z-C, Theis H, Kolb H)
WO-2005097766, 20 October 2005
New 2-aminomethylthiazole-5-carboxamide derivatives,
their compositions, and their use for the treatment of, for
example, allergy, cardiovascular disease, cancer, dental
disease, dermatological disease, endocrine disease,
metabolic disorder, gastrointestinal disease, genitourinary
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