Characterization of pharmacological efficacy of VX-148, a new, potent immunosuppressive inosine 5'-monophosphate dehydrogenase inhibitor.
Inosine 5'-monophosphate dehydrogenase (IMPDH) enzyme catalyzes the rate-limiting step in the de novo biosynthesis of guanine nucleotides. Proliferation of lymphocytes is critically dependent on this de novo nucleotide synthesis pathway. Hence, IMPDH is an attractive target for the development of immunosuppressive drugs. VX-148 is a novel, uncompetitive IMPDH inhibitor with a K(i) value of 6 nM against IMPDH type II enzyme. VX-148 is slightly more potent than mycophenolic acid and VX-497 in inhibiting the proliferation of mitogen-stimulated primary human lymphocytes (IC(50) value of ~80 nM). The inhibitory activity of VX-148 is alleviated in the presence of exogenous guanosine. VX-148 does not inhibit proliferation of nonlymphoid cell types such as fibroblasts, indicating selectivity for inhibition of IMPDH activity. VX-148 is orally bioavailable in rats and mice; oral administration of VX-148 inhibits primary antibody response in mice in a dose-dependent manner with an ED(50) value of 38 mg/kg b.i.d. VX-148 significantly prolongs skin graft survival at 100 mg/kg b.i.d. in mice. These results demonstrate that VX-148 is a potent and specific IMPDH inhibitor with a favorable pharmacokinetic profile and good pharmacological activity in mice, and thus support development of VX-148 as an immunosuppressive drug.
Jain
Jugnu
J
Vertex Pharmaceuticals, Inc., 130 Waverly Street, Cambridge, MA 02139, USA. jain@vpharm.com
Almquist
Susan J
SJ
Heiser
Angela D
AD
Shlyakhter
Dina
D
Leon
Eduardo
E
Memmott
Christine
C
Moody
Cameron Stuver
CS
Nimmesgern
Elmar
E
Decker
Caroline
C
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006462:Hemolytic Plaque Technique; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000097:blood; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008934:Mitogens / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D016038:Skin Transplantation / Q000276:immunology; D013056:Spectrophotometry, Ultraviolet; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000201:enzymology
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007202:Indicators and Reagents; D007527:Isoenzymes; D008934:Mitogens; D010671:Phenylurea Compounds; C465281:VX148; D007168:IMP Dehydrogenase