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.
Pfizer Global Research & Development, Pfizer, Inc, Groton, Connecticut 06340, USA.
Thomas V
TV
Magee
Sharon L
SL
Ripp
Bryan
B
Li
Richard A
RA
Buzon
Lou
L
Chupak
Thomas J
TJ
Dougherty
Steven M
SM
Finegan
Dennis
D
Girard
Anne E
AE
Hagen
Michael J
MJ
Falcone
Kathleen A
KA
Farley
Karl
K
Granskog
Joel R
JR
Hardink
Michael D
MD
Huband
Barbara J
BJ
Kamicker
Takushi
T
Kaneko
Michael J
MJ
Knickerbocker
Jennifer L
JL
Liras
Andrea
A
Marra
Ivy
I
Medina
Thuy-Trinh
TT
Nguyen
Mark C
MC
Noe
R Scott
RS
Obach
John P
JP
O'Donnell
Joseph B
JB
Penzien
Usa Datta
UD
Reilly
John R
JR
Schafer
Yue
Y
Shen
Gregory G
GG
Stone
Timothy J
TJ
Strelevitz
Jianmin
J
Sun
Amelia
A
Tait-Kamradt
Alfin D N
AD
Vaz
David A
DA
Whipple
Daniel W
DW
Widlicka
Donn G
DG
Wishka
Joanna P
JP
Wolkowski
Mark E
ME
Flanagan
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