3-Aminopyrrolidinone Farnesyltransferase Inhibitors: Design of Macrocyclic Compounds with Improved Pharmacokinetics and Excellent Cell Potency

Autor:	Kelly Hamilton, Michael J. Bogusky, Robert B. Lobell, Lorena S. Beese, Joel R. Huff, Samuel L. Graham, Marc Abrams, Jackson B. Gibbs, Christine Fernandes, Ronald G. Robinson, J. Christopher Culberson, Carl F. Homnick, Eileen S. Walsh, Joseph J. Lynch, David C. Heimbrook, Michelle Ellis-Hutchings, Douglas C. Beshore, Hans E. Huber, Kenneth S. Koblan, Jeffrey S. Taylor, George D. Hartman, Hema Bhimnathwala, Kelem Kassahun, Nancy E. Kohl, Theresa M. Williams, Carolyn A. Buser, A. David Rodrigues, Joseph P. Davide, C. Blair Zartman, Steven N. Gallicchio, Ian M. Bell
Rok vydání:	2002
Předmět:	Models Molecular ERG1 Potassium Channel Magnetic Resonance Spectroscopy Potassium Channels Pyrrolidines Stereochemistry Farnesyltransferase In Vitro Techniques Naphthalenes Crystallography X-Ray Mass Spectrometry Cell Line Electrocardiography Structure-Activity Relationship Dogs Transcriptional Regulator ERG In vivo Drug Discovery Animals Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme Inhibitors Farnesyltranstransferase Humans Structure–activity relationship Enzyme Inhibitors Cation Transport Proteins Farnesyl-diphosphate farnesyltransferase Alkyl and Aryl Transferases Molecular Structure biology Chemistry Oxidoreductases N-Demethylating Stereoisomerism Ether-A-Go-Go Potassium Channels Bioavailability DNA-Binding Proteins Potassium Channels Voltage-Gated Enzyme inhibitor Microsomes Liver Trans-Activators biology.protein Molecular Medicine Aryl Hydrocarbon Hydroxylases Chromatography Liquid Protein Binding
Zdroj:	Journal of Medicinal Chemistry. 45:2388-2409
ISSN:	1520-4804 0022-2623
DOI:	10.1021/jm010531d
Popis:	A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase inhibitors (FTIs) has been synthesized. Compared with previously described linear 3-aminopyrrolidinone FTIs such as compound 1, macrocycles such as 49 combined improved pharmacokinetic properties with a reduced potential for side effects. In dogs, oral bioavailability was good to excellent, and increases in plasma half-life were due to attenuated clearance. It was observed that in vivo clearance correlated with the flexibility of the molecules and this concept proved useful in the design of FTIs that exhibited low clearance, such as FTI 78. X-ray crystal structures of compounds 49 and 66 complexed with farnesyltransferase (FTase)-farnesyl diphosphate (FPP) were determined, and they provide details of the key interactions in such ternary complexes. Optimization of this 3-aminopyrrolidinone series of compounds led to significant increases in potency, providing 83 and 85, the most potent inhibitors of FTase in cells described to date.
Databáze:	OpenAIRE
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