Division of Medicinal Chemistry Abstracts-235th ACS National ...

DK226 is a conjugate of HA and methotrexate (MTX) designed to combine the advantages of
the two agents and overcome their shortcomings. Since MTX has a potent anti-inflammatory
effect, the binding ratio of MTX needed for DK226 to exert sufficient efficacy is as low as 3%,
and that makes it possible for the conjugate to preserve properties of HA, such as high
molecular weight and visco-elasticity.
In rat arthritic models, it was demonstrated that DK226 has anti-inflammatory effects and a
superior analgesic effect to conventional HA. No systemic and local toxicity have been observed
in preliminary toxicity studies. DK226, therefore, could provide a safe and effective new therapy
for the treatment of OA.
MEDI 69
Investigation of ketone warheads as alternatives to the nitrile for preparation of potent
and selective cathepsin k inhibitors
Michael J. Boyd, Sheldon N. Crane, Joel Robichaud, John Scheigetz, Cameron Black, Nathalie
Chauret, Qingping Wang, Frédéric Massé, and Renata Oballa, Medicinal Chemistry, Merck
Frosst, 16711 Trans Canada, Kirkland, QC H9H 3L1, Canada, Fax: 514-428-4900,
michael_boyd@merck.com
Osteoporosis is a condition where bone becomes thin, weak and brittle. Consequently,
osteoporosis can significantly increase the risk of bone fractures. The condition is caused by an
imbalance between bone formation and bone resorption and it is believed that the lysosomal
cysteine protease cathepsin K (Cat K) plays a key role in the degradation of the bone matrix.
More specifically, Cat K is involved in the degradation of type I collagen which is the major
component of the organic bone matrix. It has been hypothesized that Cat K inhibitors could
therefore be used in the treatment of osteoporosis, and there has been considerable effort
directed towards the development of potent and selective Cat K inhibitors over the last decade.
Most reported inhibitors of Cat K contain electrophilic “warheads” which covalently bind to the
catalytic Cys 25 residue, such as nitriles and ketones. Recently, we have reported the
development of odanacatib (MK-0822), a reversible, non-basic, potent and selective nitrile
inhibitor of Cat K. Amino ketone warheads were explored as alternatives to the nitrile group of
odanacatib. The ketones explored are potent and selective inhibitors of cathepsin K; however,
they are generally less potent and selective than odanacatib. The SAR of the series of ketones
will be discussed, as well as the effects of the nitrile replacement on metabolism and
pharmacokinetics.