Inhibitors of farnesyl protein transferase. 4-Amido, 4-carbamoyl, and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]- cyclohepta[1,2-b]pyridin-11-yl)piperazine and 1-(3-bromo-8-chloro-6,11- dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperazine.
The synthesis of a variety of novel 4-amido, 4-carbamoyl and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl) piperazine to explore the SAR of this series of FPT inhibitors is described. This resulted in the synthesis of the 4- and 3-pyridylacetyl analogues 45a and 50a, respectively, both of which were orally active but were found to be rapidly metabolized in vivo. Identification of the principal metabolites led to the synthesis of a variety of new compounds that would be less readily metabolized, the most interesting of which were the 3- and 4-pyridylacetyl N-oxides 80a and 83a. Novel replacements for the pyridylacetyl moiety were also sought, and this resulted in the discovery of the 4-N-methyl and 4-N-carboxamidopiperidinylacetyl derivatives 135a and 160a, respectively. All of these derivatives exhibited greatly improved pharmacokinetics. The synthesis of the corresponding 3-bromo analogues resulted in the discovery of the 4-pyridylacetyl N-oxides 83b (+/-) and 85b [11S(-)] and the 4-carboxamidopiperidinylacetamido derivative 160b (+/-), all of which exhibited potent FPT inhibition in vitro. All three showed excellent oral bioavailability in vivo in nude mice and cynomolgus monkeys and exhibited excellent antitumor efficacy against a series of tumor cell lines when dosed orally in nude mice.
Mallams
A K
AK
Schering-Plough Research Institute, Kenilworth, New Jersey 07033-0539, USA.
Rossman
R R
RR
Doll
R J
RJ
Girijavallabhan
V M
VM
Ganguly
A K
AK
Petrin
J
J
Wang
L
L
Patton
R
R
Bishop
W R
WR
Carr
D M
DM
Kirschmeier
P
P
Catino
J J
JJ
Bryant
M S
MS
Chen
K J
KJ
Korfmacher
W A
WA
Nardo
C
C
Wang
S
S
Nomeir
A A
AA
Lin
C C
CC
Li
Z
Z
Chen
J
J
Lee
S
S
Dell
J
J
Lipari
P
P
Liu
M
M
D016475:3T3 Cells; D000284:Administration, Oral; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D019556:COS Cells; D002461:Cell Line, Transformed; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D011905:Genes, ras; D008252:Macaca fascicularis; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D010879:Piperazines; D010880:Piperidines; C111350:Sch 59228; C111351:Sch 60627; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase