Second-generation peptidomimetic inhibitors of protein farnesyltransferase demonstrating improved cellular potency and significant in vivo efficacy.
The synthesis and evaluation of analogues of previously reported farnesyltransferase inhibitors, pyridyl benzyl ether 3 and pyridylbenzylamine 4, are described. Substitution of 3 at the 5-position of the core aryl ring resulted in inhibitors of equal or less potency against the enzyme and decreased efficacy in a cellular assay against Ras processing by the enzyme. Substitution of 4 at the benzyl nitrogen yielded 26, which showed improved efficacy and potency and yet presented a poor pharmacokinetic profile. Further modification afforded 30, which demonstrated a dramatically improved pharmacokinetic profile. Compounds 26 and 29 demonstrated significant in vivo efficacy in nude mice inoculated with MiaPaCa-2, a human pancreatic tumor-derived cell line.
O'Connor
S J
SJ
Department of Cancer Research D-47B, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
Barr
K J
KJ
Wang
L
L
Sorensen
B K
BK
Tasker
A S
AS
Sham
H
H
Ng
S C
SC
Cohen
J
J
Devine
E
E
Cherian
S
S
Saeed
B
B
Zhang
H
H
Lee
J Y
JY
Warner
R
R
Tahir
S
S
Kovar
P
P
Ewing
P
P
Alder
J
J
Mitten
M
M
Leal
J
J
Marsh
K
K
Bauch
J
J
Hoffman
D J
DJ
Sebti
S M
SM
Rosenberg
S H
SH
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001596:Benzylamines / Q000138:chemical synthesis / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004987:Ethers / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D019014:fas Receptor
D000970:Antineoplastic Agents; D001596:Benzylamines; D004791:Enzyme Inhibitors; D004987:Ethers; C491901:FAS protein, human; C491899:Fas protein, mouse; D009479:Neuropeptides; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase