Phosphate prodrugs of PD154075.
In the preparation of phosphate prodrugs of PD154075, several strategies of linking a phosphate group to the indole moiety were studied. A novel linker, p-hydroxymethylbenzoyloxymethoxycarbonyl, was discovered to provide the phosphate prodrug of PD154075 (compound 9) with significantly increased aqueous solubility, sufficient stability in aqueous solution and good bio-reconversion in vivo.
Zhu
Z
Z
Chemical Development, Parke-Davis Pharmaceutical Research, Arbor, MI 48105, USA. zhijian.zhu@wl.com
Chen
H G
HG
Goel
O P
OP
Chan
O H
OH
Stilgenbauer
L A
LA
Stewart
B H
BH
D000818:Animals; D004355:Drug Stability; D007211:Indoles / Q000737:chemistry; D008297:Male; D010755:Organophosphates / Q000138:chemical synthesis* / Q000378:metabolism*; D010710:Phosphates / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism
C413742:2-benzofuranylmethoxycarboyl-alpha-methyl-1'-((4-(phosphoryloxymethyl)benzoyl)methoxycarbonyl)tryptophan-N-(1-phenylethyl)amide; D007211:Indoles; D010755:Organophosphates; D010710:Phosphates; D011355:Prodrugs; D014364:Tryptophan; C089683:PD 154075