title: Development of serine protease inhibitors displaying a multicentered short (<2.3 A) hydrogen bond binding mode: inhibitors of urokinase-type plasminogen activator and factor Xa.
abstract: Novel scaffolds that bind to serine proteases through a unique network of short hydrogen bonds to the catalytic Ser195 have been developed. The resulting potent serine protease inhibitors were designed from lead molecule 2-(2-hydroxyphenyl)1H-benzoimidazole-5-carboxamidine, 6b, which is known to display several modes of binding. For instance, 6b can recruit zinc and bind in a manner similar to that reported by bis(5-amidino-2-benzimidazolyl)methane (BABIM) (Nature 1998, 391, 608-612).(1) Alternatively, 6b can bind in the absence of zinc through a multicentered network of short (<2.3 A) hydrogen bonds. The lead structure was optimized in the zinc-independent binding mode toward a panel of six human serine proteases to yield optimized inhibitors such as 2-(3-bromo-2-hydroxy-5-methylphenyl)-1H-indole-5-carboxamidine, 22a, and 2-(2-hydroxybiphenyl-3-yl)-1H-indole-5-carboxamidine, 22f. Structure-activity relationships determined that, apart from the amidine function, an indole or benzimidazole and an ortho substituted phenol group were also essential components for optimal potency. The affinities (K(i)) of 22a and 22f, for example, bearing these groups ranged from 8 to 600 nM toward a panel of six human serine proteases. High-resolution crystal structures revealed that the binding mode of these molecules in several of the enzymes was identical to that of 6b and involved short (<2.3 A) hydrogen bonds among the inhibitor hydroxyl oxygen, Ser195, and a water molecule trapped in the oxyanion hole. In summation, novel and potent trypsin-like serine protease inhibitors possessing a unique mode of binding have been discovered.
authors.affiliation: Department of Medicinal Chemistry, Axys Pharmaceuticals Inc., 180 Kimball Way, South San Francisco, California 94080, USA.
authors.forename: E
authors.initials: E
authors.lastname: Verner
authors.forename: B A
authors.initials: BA
authors.lastname: Katz
authors.forename: J R
authors.initials: JR
authors.lastname: Spencer
authors.forename: D
authors.initials: D
authors.lastname: Allen
authors.forename: J
authors.initials: J
authors.lastname: Hataye
authors.forename: W
authors.initials: W
authors.lastname: Hruzewicz
authors.forename: H C
authors.initials: HC
authors.lastname: Hui
authors.forename: A
authors.initials: A
authors.lastname: Kolesnikov
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: C
authors.initials: C
authors.lastname: Luong
authors.forename: A
authors.initials: A
authors.lastname: Martelli
authors.forename: K
authors.initials: K
authors.lastname: Radika
authors.forename: R
authors.initials: R
authors.lastname: Rai
authors.forename: M
authors.initials: M
authors.lastname: She
authors.forename: W
authors.initials: W
authors.lastname: Shrader
authors.forename: P A
authors.initials: PA
authors.lastname: Sprengeler
authors.forename: S
authors.initials: S
authors.lastname: Trapp
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: W B
authors.initials: WB
authors.lastname: Young
authors.forename: R L
authors.initials: RL
authors.lastname: Mackman
mesh_terms: D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D065427:Factor Xa Inhibitors; D006801:Humans; D006860:Hydrogen Bonding; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors*
chemical_list: C433826:2-(2-hydroxybiphenyl-3-yl)-1H-indole-5-carboxamidine; C433825:2-(3-bromo-2-hydroxy-5-methylphenyl)-1H-indole-5-carboxamidine; D000578:Amidines; D065427:Factor Xa Inhibitors; D007211:Indoles; D015842:Serine Proteinase Inhibitors; D014568:Urokinase-Type Plasminogen Activator