title: Investigation of ketone warheads as alternatives to the nitrile for preparation of potent and selective cathepsin K inhibitors.
abstract: 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.
authors.affiliation: 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
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Boyd
authors.forename: Sheldon N
authors.initials: SN
authors.lastname: Crane
authors.forename: Joël
authors.initials: J
authors.lastname: Robichaud
authors.forename: John
authors.initials: J
authors.lastname: Scheigetz
authors.forename: W Cameron
authors.initials: WC
authors.lastname: Black
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chauret
authors.forename: Qingping
authors.initials: Q
authors.lastname: Wang
authors.forename: Frédéric
authors.initials: F
authors.lastname: Massé
authors.forename: Renata M
authors.initials: RM
authors.lastname: Oballa
mesh_terms: 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
chemical_list: D001713:Biphenyl Compounds; D007659:Ketones; D009570:Nitriles; D056657:Cathepsin K; C527128:odanacatib