title: Bis-aryl urea derivatives as potent and selective LIM kinase (Limk) inhibitors.
abstract: The discovery/optimization of bis-aryl ureas as Limk inhibitors to obtain high potency and selectivity and appropriate pharmacokinetic properties through systematic SAR studies is reported. Docking studies supported the observed SAR. Optimized Limk inhibitors had high biochemical potency (IC50 < 25 nM), excellent selectivity against ROCK and JNK kinases (>400-fold), potent inhibition of cofilin phosphorylation in A7r5, PC-3, and CEM-SS T cells (IC50 < 1 μM), and good in vitro and in vivo pharmacokinetic properties. In the profiling against a panel of 61 kinases, compound 18b at 1 μM inhibited only Limk1 and STK16 with ≥80% inhibition. Compounds 18b and 18f were highly efficient in inhibiting cell-invasion/migration in PC-3 cells. In addition, compound 18w was demonstrated to be effective on reducing intraocular pressure (IOP) on rat eyes. Taken together, these data demonstrated that we had developed a novel class of bis-aryl urea derived potent and selective Limk inhibitors.
authors.affiliation: Medicinal Chemistry, ‡Discovery Biology, §Crystallography/Modeling Facility, Translational Research Institute, ∥Department of Molecular Therapeutics, and ⊥Department of Cancer Biology, The Scripps Research Institute, Scripps Florida , 130 Scripps Way, No. 2A1, Jupiter, Florida 33458, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yin
authors.forename: Ke
authors.initials: K
authors.lastname: Zheng
authors.forename: Nibal
authors.initials: N
authors.lastname: Eid
authors.forename: Shannon
authors.initials: S
authors.lastname: Howard
authors.forename: Ji-Hak
authors.initials: JH
authors.lastname: Jeong
authors.forename: Fei
authors.initials: F
authors.lastname: Yi
authors.forename: Jia
authors.initials: J
authors.lastname: Guo
authors.forename: Chul Min
authors.initials: CM
authors.lastname: Park
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bibian
authors.forename: Weilin
authors.initials: W
authors.lastname: Wu
authors.forename: Pamela
authors.initials: P
authors.lastname: Hernandez
authors.forename: HaJeung
authors.initials: H
authors.lastname: Park
authors.forename: Yuntao
authors.initials: Y
authors.lastname: Wu
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Luo
authors.forename: Philip V
authors.initials: PV
authors.lastname: LoGrasso
authors.forename: Yangbo
authors.initials: Y
authors.lastname: Feng
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D054461:Lim Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D014508:Urea; D054461:Lim Kinases