Design and synthesis of piperidine farnesyltransferase inhibitors with reduced glucuronidation potential

• Published in: Bioorganic & medicinal chemistry Vol. 15; no. 3; pp. 1363 - 1382
• Main Authors: Tanaka, Rieko, Rubio, Almudena, Harn, Nancy K., Gernert, Douglas, Grese, Timothy A., Eishima, Jun, Hara, Mitsunobu, Yoda, Nobuyuki, Ohashi, Rui, Kuwabara, Takashi, Soga, Shiro, Akinaga, Shiro, Nara, Shinji, Kanda, Yutaka
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-02-2007; Elsevier Science
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Animals; Antineoplastic agents; Biological and medical sciences; Crystallography, X-Ray; Design and synthesis; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Farnesyltransferase (FTase) inhibitors; General aspects; Glucuronides - metabolism; Medical sciences; Mice; Microsomes, Liver - metabolism; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Piperidine derivatives; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Protein Prenylation; Rats; Reduced glucuronidation; Structure-Activity Relationship; Farnesyltransferase (FTase) inhibitors; Reduced glucuronidation; Piperidine derivatives; Design and synthesis; Antineoplastic agent; Nitro compound; Sulfonamide; Enzyme; Transferases; Enzyme inhibitor; Glucuronic acid conjugation; Inhibitor enzyme complex; Farnesyl-diphosphate farnesyltransferase; In vitro; Modeling; Pyridine derivatives; Resistance; Structure activity relation; Molecular model; Binding mode; Phenols; Benzenic compound; Chemical synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.11.007

Metabolically stable compound
20a with potent FTase inhibition (IC
50
=
3
nM) is reported.
The design and synthesis of a novel piperidine series of farnesyltransferase (FTase) inhibitors with reduced potential for metabolic glucuronidation are described. The various substitution and exchange of the phenyl group at the C-2 position of the previously described 2-(4-hydroxy)phenyl-3-nitropiperidine
1a (FTase IC
50
=
5.4
nM) resulted in metabolically stable compounds with potent FTase inhibition (
14a IC
50
=
4.3
nM,
20a IC
50
=
3.0
nM, and
50a IC
50
=
16
nM). Molecular modeling studies of these compounds complexed with FTase and farnesyl pyrophosphate are also described.