Discovery of azetidinyl ketolides for the treatment of susceptible and multidrug resistant community-acquired respiratory tract infections.
Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.
Magee
Thomas V
TV
Pfizer Global Research & Development, Pfizer, Inc, Groton, Connecticut 06340, USA.
Ripp
Sharon L
SL
Li
Bryan
B
Buzon
Richard A
RA
Chupak
Lou
L
Dougherty
Thomas J
TJ
Finegan
Steven M
SM
Girard
Dennis
D
Hagen
Anne E
AE
Falcone
Michael J
MJ
Farley
Kathleen A
KA
Granskog
Karl
K
Hardink
Joel R
JR
Huband
Michael D
MD
Kamicker
Barbara J
BJ
Kaneko
Takushi
T
Knickerbocker
Michael J
MJ
Liras
Jennifer L
JL
Marra
Andrea
A
Medina
Ivy
I
Nguyen
Thuy-Trinh
TT
Noe
Mark C
MC
Obach
R Scott
RS
O'Donnell
John P
JP
Penzien
Joseph B
JB
Reilly
Usa Datta
UD
Schafer
John R
JR
Shen
Yue
Y
Stone
Gregory G
GG
Strelevitz
Timothy J
TJ
Sun
Jianmin
J
Tait-Kamradt
Amelia
A
Vaz
Alfin D N
AD
Whipple
David A
DA
Widlicka
Daniel W
DW
Wishka
Donn G
DG
Wolkowski
Joanna P
JP
Flanagan
Mark E
ME
D000818:Animals; D001384:Azetidines / Q000737:chemistry*; D001419:Bacteria / Q000187:drug effects; D017714:Community-Acquired Infections / Q000188:drug therapy; D004198:Disease Susceptibility; D055808:Drug Discovery; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D048628:Ketolides / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008826:Microbial Sensitivity Tests; D012141:Respiratory Tract Infections / Q000188:drug therapy*
D001384:Azetidines; D048628:Ketolides; C082735:azetidine; C106791:telithromycin