Novel mycophenolic adenine bis(phosphonate)s as potential immunosuppressants.
Mycophenolic acid (MPA) is the most potent and specific inhibitor of inosine monophosphate dehydrogenase (IMPDH). This compound was reported to bind the NAD site of IMPDH and mimic the binding of nicotinamide moiety of nicotinamide adenine dicnucleotide. We linked MPA derivatives with the adenine moiety of NAD through a methylenebis(phonphonate) birdge to form novel mycophenolic adenine dinucleotides (MADs) which resemble well the intact natural cofactor. The MAD analogues differ by the length of the side chain (linker) between the aromatic ring of mycophenolic derivative and the beta-phosphorus atom of the adenosine bis(phosphonate) moiety. Regardless of the linker size, MADs were found to be potent inhibitors of human IMPDH type I and type II with Ki's = 0.25-0.52 microM, an order of magnitude less potent than MPA itself (Ki = 0.01-0.04 microM). The growth of K562 cells was inhibited by MPA (IC50 = 0.03 microM) and the MAD analogues (IC50 = 0.01-1.15 microM) with a similar potency. Accordingly, a suppression of alloantigen- induced proliferation of human lymphocytes by the MAD analogues at concentration of 10-20 microM was equally effective as that observed for MPA. In contrast to MPA, MAD analogues were found to be resistant to glucuronidation in vitro. Since therapeutic potential of MPA is limited by its undesirable glucuronidation, the glucuronidation- resistant MAD analogues may be superior immunosuppressants if they are not glucuronidated in vivo.
Pankiewicz
K W
KW
Pharmasset, Inc., 1860 Montreal Road, Atlanta, GA 30084, USA.
Lesiak-Watanabe
K
K
Watanabe
K A
KA
Malinowski
K
K
D004305:Dose-Response Relationship, Drug; D019073:HT29 Cells; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D020014:K562 Cells; D007700:Kinetics; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D009243:NAD / Q000031:analogs & derivatives
C121449:C2-mycophenolic adenine dinucleotide; C121448:C4-mycophenolic adenine dinucleotide; C121447:C6-mycophenolic adenine dinucleotide; D007166:Immunosuppressive Agents; D009243:NAD; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid