title: Orally active desulfated low molecular weight heparin and deoxycholic acid conjugate, 6ODS-LHbD, suppresses neovascularization and bone destruction in arthritis.
abstract: The regulation of angiogenesis is an interesting area to consider for novel therapeutic approaches to rheumatoid arthritis (RA). Chemically modified heparins have been developed as possible candidates for angiogenesis inhibitor; however, they have a major clinical drawback in exhibiting poor oral bioavailability. Here, orally absorbable O-desulfated low molecular weight heparin (ODS-LMWH) derivatives were newly synthesized by conjugating 2-O- or 6-O-desulfated LMWH with deoxycholic acid (DOCA) or bisDOCA (a dimer of DOCA), and their physicochemical properties, antiangiogenic potency and pharmacokinetic profiles were assessed. After selecting the best candidate among those derivatives, its therapeutic efficacy on arthritis was investigated in a murine collagen antibody-induced arthritis (CAIA) model. ODS-LMWH derivatives significantly inhibited the capillary-like tube formation of human umbilical vein endothelial cells (HUVECs) and basic fibroblast growth factor (bFGF)-induced angiogenesis in the Matrigel plug assay. Among all the compounds, 6ODS-LHbD showed the highest oral bioavailability in rats (19.3%). In the CAIA mouse model, 6ODS-LHbD (10 mg/kg, p.o., S.I.D.) significantly inhibited neovascularization in the joint, the increase of hind-paw thickness, and the structural damage in the bone. Therefore, 6ODS-LHbD would be a promising candidate for an orally active drug for the treatment of RA.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Seung Rim
authors.initials: SR
authors.lastname: Hwang
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Seo
authors.forename: Taslim A
authors.initials: TA
authors.lastname: Al-Hilal
authors.forename: Ok-Cheol
authors.initials: OC
authors.lastname: Jeon
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Kang
authors.forename: Sung-Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Han Sung
authors.initials: HS
authors.lastname: Kim
authors.forename: Young-Tae
authors.initials: YT
authors.lastname: Chang
authors.forename: Young Mo
authors.initials: YM
authors.lastname: Kang
authors.forename: Victor C
authors.initials: VC
authors.lastname: Yang
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D001862:Bone Resorption / Q000188:drug therapy / Q000473:pathology; D003840:Deoxycholic Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D017207:Rats, Sprague-Dawley; D013455:Sulfur / Q000737:chemistry
chemical_list: D020533:Angiogenesis Inhibitors; D006495:Heparin, Low-Molecular-Weight; D003840:Deoxycholic Acid; D013455:Sulfur