Linked Life Data

11288107

Source:http://linkedlifedata.com/resource/pubmed/id/11288107

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2001-4-5
pubmed:abstractText
Inosine monophosphate dehydrogenase (IMPDH) is an essential rate-limiting enzyme in the purine metabolic pathway, catalyzing the de novo synthesis of guanine nucleotides required for lymphocyte proliferation. IMPDH has therefore been an attractive target for developing immunosuppressive drugs (e.g., CellCept and mizoribine). Here we describe the immunosuppressive activity of VX-497, a novel noncompetitive inhibitor of IMPDH. VX-497 (MW 452.5) is orally bioavailable and inhibits the proliferation of primary human, mouse, rat, and dog lymphocytes at concentrations of approximately 100 nM. The inhibitory effect of VX-497 on lymphocytes is reversed in the presence of exogenous guanosine, but not in the presence of adenosine or uridine, confirming that the antilymphocytic activity of VX-497 is specifically due to inhibition of IMPDH. The antiproliferative effect of VX-497 in cells is also reversed within 48 h of its removal. Based on evaluation of VX-497 in several lymphoid and nonlymphoid cells, the antiproliferative effect of VX-497 is observed to be most pronounced on lymphoid and keratinocyte cells as compared with fibroblasts. In vivo, oral administration of VX-497 inhibits the primary IgM antibody response in a dose-dependent manner, with an ED(50) value of approximately 30-35 mg/kg in mice. Single daily dosing of VX-497 is observed to be as effective as twice-daily dosing in this model of immune activation. These studies demonstrate that VX-497 is a potent, specific, and reversible IMPDH inhibitor that selectively inhibits lymphocyte proliferation.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0022-3549
pubmed:author
pubmed:copyrightInfo
Copyright 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association.
pubmed:issnType
Print
pubmed:volume
90
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
625-37
pubmed:dateRevised
2004-11-17
pubmed:meshHeading
pubmed:year
2001
pubmed:articleTitle
VX-497: a novel, selective IMPDH inhibitor and immunosuppressive agent.
pubmed:affiliation
Cell Biology and Immunology, Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, Massachusetts 02139, USA. Jugnu_Jain@vpharm.com
pubmed:publicationType
Journal Article