Exploring the role of bromine at C(10) of (+)-4-[2-[4-(8-chloro-3,10-dibromo- 6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(R)-yl)-1-piperidinyl]-2- oxoethyl]-1-piperidinecarboxamide (Sch-66336): the discovery of indolocycloheptapyridine inhibitors of farnesyl protein transferase.
The 10-bromobenzocycloheptapyridyl farnesyl transferase inhibitor (FTI) Sch-66336 (1) is currently under clinical evaluation for the treatment of human cancers. During structure-activity relationship development leading to 1, 10-bromobenzocycloheptapyridyl FTIs were found to be more potent than analogous compounds lacking the 10-Br substituent. This potency enhancement was believed to be due, in part, to an increase in conformational rigidity as the 10-bromo substituent could restrict the conformation of the appended C(11) piperidyl substituent in an axial orientation. A novel and potent class of FTIs, represented by indolocycloheptapyridine Sch-207758 [(+)-10a], have been designed based on this principle. Although structural and thermodynamic results suggest that entropy plays a crucial role in the increased potency observed with (+)-10a through conformational constraints and solvation effects, the results also indicate that the indolocycloheptapyridine moiety in (+)-10a provides increased hydrophobic interactions with the protein through the addition of the indole group. This report details the X-ray structure and the thermodynamic and pharmacokinetic profiles of (+)-10a, as well as the synthesis of indolocycloheptapyridine FTIs and their potencies in biochemical and biological assays.
Department of Chemistry and Tumor Biology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. arthur.taveras@spcorp.com
Arthur G
AG
Taveras
Cynthia
C
Aki
Jianping
J
Chao
Ronald J
RJ
Doll
Tarik
T
Lalwani
Viyyoor
V
Girijavallabhan
Corey L
CL
Strickland
William T
WT
Windsor
Patricia
P
Weber
Frank
F
Hollinger
Mark
M
Snow
Robert
R
Patton
Paul
P
Kirschmeier
Linda
L
James
Ming
M
Liu
Amin
A
Nomeir
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001966:Bromine / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006207:Half-Life; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D000970:Antineoplastic Agents; D001966:Bromine; D004791:Enzyme Inhibitors; D007211:Indoles; D010880:Piperidines; D011725:Pyridines; C064911:p21(ras) farnesyl-protein transferase; C115354:lonafarnib; D003986:Dibenzocycloheptenes