3-Aminopyrrolidinone farnesyltransferase inhibitors: design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency.
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.
Bell
Ian M
IM
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. ian_bell@merck.com
Gallicchio
Steven N
SN
Abrams
Marc
M
Beese
Lorena S
LS
Beshore
Douglas C
DC
Bhimnathwala
Hema
H
Bogusky
Michael J
MJ
Buser
Carolyn A
CA
Culberson
J Christopher
JC
Davide
Joseph
J
Ellis-Hutchings
Michelle
M
Fernandes
Christine
C
Gibbs
Jackson B
JB
Graham
Samuel L
SL
Hamilton
Kelly A
KA
Hartman
George D
GD
Heimbrook
David C
DC
Homnick
Carl F
CF
Huber
Hans E
HE
Huff
Joel R
JR
Kassahun
Kelem
K
Koblan
Kenneth S
KS
Kohl
Nancy E
NE
Lobell
Robert B
RB
Lynch
Joseph J
JJ
Robinson
Ronald
R
Rodrigues
A David
AD
Taylor
Jeffrey S
JS
Walsh
Eileen S
ES
Williams
Theresa M
TM
Zartman
C Blair
CB
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
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