Investigation of ketone warheads as alternatives to the nitrile for preparation of potent and selective cathepsin K inhibitors.
Amino ketone warheads were explored as alternatives to the nitrile group of a potent and selective cathepsin K inhibitor. The resulting compounds were potent and selective inhibitors of cathepsin K and these nitrile replacements had a significant effect on metabolism and pharmacokinetics.
Boyd
Michael J
MJ
Merck Frosst Centre for Therapeutic Research, Medicinal Chemistry, 16711 Trans Canada Hwy, PO Box 1005, Pointe-Claire-Dorval, Que., Canada H9R 4P8. michael_boyd@merck.com
Crane
Sheldon N
SN
Robichaud
Joël
J
Scheigetz
John
J
Black
W Cameron
WC
Chauret
Nathalie
N
Wang
Qingping
Q
Massé
Frédéric
F
Oballa
Renata M
RM
D000818:Animals; D001646:Bile / Q000378:metabolism; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D056657:Cathepsin K / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D007659:Ketones / Q000032:analysis / Q000737:chemistry*; D008956:Models, Chemical; D009570:Nitriles / Q000737:chemistry*; D010024:Osteoporosis / Q000188:drug therapy; D051381:Rats; D013329:Structure-Activity Relationship; D013997:Time Factors
D001713:Biphenyl Compounds; D007659:Ketones; D009570:Nitriles; D056657:Cathepsin K; C527128:odanacatib