Identification of pharmacokinetically stable 3, 10-dibromo-8-chlorobenzocycloheptapyridine farnesyl protein transferase inhibitors with potent enzyme and cellular activities.
Farnesyl protein transferase (FPT) is a promising target for the development of cancer chemotherapeutics because it is responsible for the farnesylation of oncogenic p21 Ras proteins which are found in nearly 30% of all human cancers and necessary for cellular development and growth. The recent discovery and progression to phase II clinical trials of trihalobenzocycloheptapyridine Sch-66336 as a potent inhibitor of FPT with oral, in vivo efficacy in mice have spawned extensive structure-activity relationship studies (SAR) of this class of compounds. Of the many trihalobenzocycloheptapyridine analogues prepared, we have identified several which inhibit FPT and cellular proliferation at single-digit nanomolar concentrations and which have good pharmacokinetic properties in mice.
Taveras
A G
AG
Anti-infectives and Tumor Biology Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA.
Deskus
J
J
Chao
J
J
Vaccaro
C J
CJ
Njoroge
F G
FG
Vibulbhan
B
B
Pinto
P
P
Remiszewski
S
S
del Rosario
J
J
Doll
R J
RJ
Alvarez
C
C
Lalwani
T
T
Mallams
A K
AK
Rossman
R R
RR
Afonso
A
A
Girijavallabhan
V M
VM
Ganguly
A K
AK
Pramanik
B
B
Heimark
L
L
Bishop
W R
WR
Wang
L
L
Kirschmeier
P
P
James
L
L
Carr
D
D
Liu
M
M
D000284:Administration, Oral; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D001682:Biological Availability; D019556:COS Cells; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000882:Haplorhini; D051379:Mice; D008819:Mice, Nude; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D017368:Protein Prenylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013453:Sulfonylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D004791:Enzyme Inhibitors; D010880:Piperidines; D016283:Proto-Oncogene Proteins p21(ras); D011725:Pyridines; D013449:Sulfonamides; D013453:Sulfonylurea Compounds; C064911:p21(ras) farnesyl-protein transferase; C115354:lonafarnib; D003986:Dibenzocycloheptenes