title: Discovery of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates: novel and highly selective aggrecanase inhibitors.
abstract: Aggrecanases, particularly aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5), are believed to be key enzymes involved in the articular cartilage breakdown that leads to osteoarthritis. Thus, aggrecanases are considered to be viable drug targets for the treatment of this debilitating disease. A series of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates was discovered to be potent, highly selective, and orally bioavailable aggrecanase inhibitors. These compounds have unique P1' groups comprising novel piperidine- or piperazine-based heterocycles that are connected to a cyclopropane amino acid scaffold via a sulfamido linkage. These P1' groups are quite effective in imparting selectivity over other MMPs, and this selectivity was further increased by incorporation of a methyl substituent in the 2-position of the cyclopropane ring. In contrast to classical hydroxamate-based inhibitors that tend to lack metabolic stability, our aggrecanase inhibitors bear a carboxylate zinc-binding group and have good oral bioavailability. Lead compound 13b, characterized by the novel P1' portion of 1,2,3,4-tetrahydropyrido[3',4':4,5]imidazo[1,2-a]pyridine ring, is a potent and selective aggrecanse inhibitor with excellent pharmacokinetic profiles.
authors.affiliation: Chemical Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Takatsuki, Osaka, Japan. makoto.shiozaki@jt.com
authors.forename: Makoto
authors.initials: M
authors.lastname: Shiozaki
authors.forename: Katsuya
authors.initials: K
authors.lastname: Maeda
authors.forename: Tomoya
authors.initials: T
authors.lastname: Miura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kotoku
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Isamu
authors.initials: I
authors.lastname: Matsuda
authors.forename: Kenta
authors.initials: K
authors.lastname: Aoki
authors.forename: Katsutaka
authors.initials: K
authors.lastname: Yasue
authors.forename: Hiroto
authors.initials: H
authors.lastname: Imai
authors.forename: Minoru
authors.initials: M
authors.lastname: Ubukata
authors.forename: Akira
authors.initials: A
authors.lastname: Suma
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yokota
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hotta
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tanaka
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Hase
authors.forename: Julia
authors.initials: J
authors.lastname: Haas
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Fryer
authors.forename: Ellen R
authors.initials: ER
authors.lastname: Laird
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Littmann
authors.forename: Steven W
authors.initials: SW
authors.lastname: Andrews
authors.forename: John A
authors.initials: JA
authors.lastname: Josey
authors.forename: Takayuki
authors.initials: T
authors.lastname: Mimura
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shinozaki
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yoshiuchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Inaba
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D055808:Drug Discovery; D010450:Endopeptidases / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D003521:Cyclopropanes; D004791:Enzyme Inhibitors; C030797:cyclopropane; D010450:Endopeptidases; C083641:aggrecanase