title: Improving potency and selectivity of a new class of non-Zn-chelating MMP-13 inhibitors.
abstract: Discovery and optimization of potency and selectivity of a non-Zn-chelating MMP-13 inhibitor with the aid of protein co-crystal structural information is reported. This inhibitor was observed to have a binding mode distinct from previously published MMP-13 inhibitors. Potency and selectivity were improved by extending the hit structure out from the active site into the S1' pocket.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Department of Medicinal Chemistry, 900 Ridgebury Rd, Ridgefield, CT 06877, USA. alexander.heim-riether@boehringer-ingelheim.com
authors.forename: Alexander
authors.initials: A
authors.lastname: Heim-Riether
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Taylor
authors.forename: Shuang
authors.initials: S
authors.lastname: Liang
authors.forename: Donghong Amy
authors.initials: DA
authors.lastname: Gao
authors.forename: Zhaoming
authors.initials: Z
authors.lastname: Xiong
authors.forename: E
authors.initials: E
authors.lastname: Michael August
authors.forename: Brandon K
authors.initials: BK
authors.lastname: Collins
authors.forename: Bennett T
authors.initials: BT
authors.lastname: Farmer
authors.forename: Kathleen
authors.initials: K
authors.lastname: Haverty
authors.forename: Melissa
authors.initials: M
authors.lastname: Hill-Drzewi
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Junker
authors.forename: S
authors.initials: S
authors.lastname: Mariana Margarit
authors.forename: Neil
authors.initials: N
authors.lastname: Moss
authors.forename: Thomas
authors.initials: T
authors.lastname: Neumann
authors.forename: John R
authors.initials: JR
authors.lastname: Proudfoot
authors.forename: Lana Smith
authors.initials: LS
authors.lastname: Keenan
authors.forename: Renate
authors.initials: R
authors.lastname: Sekul
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Neil A
authors.initials: NA
authors.lastname: Farrow
mesh_terms: D020134:Catalytic Domain; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D002614:Chelating Agents; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D053509:Matrix Metalloproteinase 13