title: 3-Aminopyrrolidinone farnesyltransferase inhibitors: design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. ian_bell@merck.com
authors.forename: Ian M
authors.initials: IM
authors.lastname: Bell
authors.forename: Steven N
authors.initials: SN
authors.lastname: Gallicchio
authors.forename: Marc
authors.initials: M
authors.lastname: Abrams
authors.forename: Lorena S
authors.initials: LS
authors.lastname: Beese
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Beshore
authors.forename: Hema
authors.initials: H
authors.lastname: Bhimnathwala
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bogusky
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Buser
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Culberson
authors.forename: Joseph
authors.initials: J
authors.lastname: Davide
authors.forename: Michelle
authors.initials: M
authors.lastname: Ellis-Hutchings
authors.forename: Christine
authors.initials: C
authors.lastname: Fernandes
authors.forename: Jackson B
authors.initials: JB
authors.lastname: Gibbs
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Hamilton
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: David C
authors.initials: DC
authors.lastname: Heimbrook
authors.forename: Carl F
authors.initials: CF
authors.lastname: Homnick
authors.forename: Hans E
authors.initials: HE
authors.lastname: Huber
authors.forename: Joel R
authors.initials: JR
authors.lastname: Huff
authors.forename: Kelem
authors.initials: K
authors.lastname: Kassahun
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Koblan
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Kohl
authors.forename: Robert B
authors.initials: RB
authors.lastname: Lobell
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: Ronald
authors.initials: R
authors.lastname: Robinson
authors.forename: A David
authors.initials: AD
authors.lastname: Rodrigues
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Taylor
authors.forename: Eileen S
authors.initials: ES
authors.lastname: Walsh
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Williams
authors.forename: C Blair
authors.initials: CB
authors.lastname: Zartman
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D027682:Cation Transport Proteins; D002460:Cell Line; D002853:Chromatography, Liquid; D018360:Crystallography, X-Ray; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004268:DNA-Binding Proteins; D004285:Dogs; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051638:Ether-A-Go-Go Potassium Channels; D051231:Farnesyltranstransferase; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors; D015221:Potassium Channels / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
chemical_list: D027682:Cation Transport Proteins; D065607:Cytochrome P-450 Enzyme Inhibitors; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D009281:Naphthalenes; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011759:Pyrrolidines; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase