title: O-phenyl carbamate and phenyl urea thiiranes as selective matrix metalloproteinase-2 inhibitors that cross the blood-brain barrier.
abstract: Brain metastasis occurs in 20-40% of cancer patients. Treatment is mostly palliative, and the inability of most drugs to penetrate the brain presents one of the greatest challenges in the development of therapeutics for brain metastasis. Matrix metalloproteinase-2 (MMP-2) plays important roles in invasion and vascularization of the central nervous system and represents a potential target for treatment of brain metastasis. Carbonate, O-phenyl carbamate, urea, and N-phenyl carbamate derivatives of SB-3CT, a selective and potent gelatinase inhibitor, were synthesized and evaluated. The O-phenyl carbamate and urea variants were selective and potent inhibitors of MMP-2. Carbamate 5b was metabolized to the potent gelatinase inhibitor 2, which was present at therapeutic concentrations in the brain. In contrast, phenyl urea 6b crossed the blood-brain barrier, however, higher doses would result in therapeutic brain concentrations. Carbamate 5b and urea 6b show potential for intervention of MMP-2-dependent diseases such as brain metastasis.
authors.affiliation: †Department of Chemistry and Biochemistry, ‡Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Major
authors.initials: M
authors.lastname: Gooyit
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.forename: Kiran V
authors.initials: KV
authors.lastname: Mahasenan
authors.forename: Katerina
authors.initials: K
authors.lastname: Lichtenwalter
authors.forename: Mark A
authors.initials: MA
authors.lastname: Suckow
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Schroeder
authors.forename: William R
authors.initials: WR
authors.lastname: Wolter
authors.forename: Shahriar
authors.initials: S
authors.lastname: Mobashery
authors.forename: Mayland
authors.initials: M
authors.lastname: Chang
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D019800:Phenol / Q000737:chemistry; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: C586845:1-ethyl-3-(4-(4-((thiiran-2-ylmethyl)sulfonyl)phenoxy)phenyl)urea; C586844:4-(4-((thiiran-2-ylmethyl)sulfonyl)phenoxy)phenyl ethylcarbamate; D002219:Carbamates; D006573:Heterocyclic Compounds, 1-Ring; D061965:Matrix Metalloproteinase Inhibitors; D010671:Phenylurea Compounds; D013440:Sulfides; D019800:Phenol; C580738:N-phenylurea; C013523:ethylene sulfide; D020778:Matrix Metalloproteinase 2
references.citation: J Phys Chem B. 2010 Jan 21;114(2):1030-7
references.pmid: 20039633
references.citation: ACS Med Chem Lett. 2012 Jun 14;3(6):490-495
references.pmid: 22737278
references.citation: J Biol Chem. 2005 Oct 7;280(40):33992-4002
references.pmid: 16046398
references.citation: Nat Rev Cancer. 2006 Mar;6(3):227-39
references.pmid: 16498445
references.citation: J Med Chem. 2004 Mar 25;47(7):1739-49
references.pmid: 15027865
references.citation: ACS Chem Neurosci. 2012 Oct 17;3(10):730-6
references.pmid: 23077716
references.citation: Int J Clin Exp Pathol. 2010 Oct 16;3(8):775-81
references.pmid: 21151391
references.citation: Nat Rev Mol Cell Biol. 2007 Mar;8(3):221-33
references.pmid: 17318226
references.citation: Acta Neuropathol. 2012 Feb;123(2):205-22
references.pmid: 22212630
references.citation: J Med Chem. 2000 Oct 5;43(20):3653-64
references.pmid: 11020279
references.citation: Cancer Res. 2006 Mar 15;66(6):3188-96
references.pmid: 16540670
references.citation: Biochem Res Int. 2011;2011:191670
references.pmid: 21152183
references.citation: J Med Chem. 2009 Feb 26;52(4):1040-9
references.pmid: 19173605
references.citation: Nat Rev Cancer. 2002 Mar;2(3):161-74
references.pmid: 11990853
references.citation: J Clin Oncol. 2004 Jul 15;22(14):2865-72
references.pmid: 15254054
references.citation: Eur J Med Chem. 2009 Jul;44(7):2994-3008
references.pmid: 19232787
references.citation: Drug Discov Today. 2007 Jan;12(1-2):54-61
references.pmid: 17198973
references.citation: Pharm Res. 2012 Mar;29(3):770-81
references.pmid: 22011930
references.citation: Int J Cancer. 1996 Feb 20;69(1):9-16
references.pmid: 8600068
references.citation: Cancer. 1998 Sep 15;83(6):1153-62
references.pmid: 9740080
references.citation: Chem Biol Drug Des. 2007 Nov;70(5):371-82
references.pmid: 17927722
references.citation: NeuroRx. 2005 Jan;2(1):3-14
references.pmid: 15717053
references.citation: J Clin Oncol. 2011 May 20;29(15):e443-5
references.pmid: 21422405
references.citation: Clin Cancer Res. 2007 Mar 15;13(6):1663-74
references.pmid: 17363519
references.citation: J Med Chem. 2011 Oct 13;54(19):6676-90
references.pmid: 21866961
references.citation: Am J Pathol. 2007 Jun;170(6):2100-11
references.pmid: 17525276
references.citation: Chem Biol Drug Des. 2009 Dec;74(6):527-34
references.pmid: 19807733
references.citation: Cancer. 1998 Feb 15;82(4):642-50
references.pmid: 9477095
references.citation: Chem Biol Drug Des. 2009 Dec;74(6):535-46
references.pmid: 19824893
references.citation: Prostate. 2000 Jan;42(1):18-25
references.pmid: 10579795
references.citation: Biochim Biophys Acta. 2013 Jan;1835(1):61-75
references.pmid: 23142311