Solubility-driven optimization of phosphodiesterase-4 inhibitors leading to a clinical candidate.
The solubility-driven optimization of a series of 1,7-napthyridine phosphodiesterase-4 inhibitors is described. Directed structural changes resulted in increased aqueous solubility, enabling superior pharmacokinetic properties with retention of PDE4 inhibition. A range of potent and orally bioavailable compounds with good in vivo efficacy in animal models of inflammation and reduced emetic potential compared to previously described drugs were synthesized. Compound 2d was taken forward as a clinical candidate for the treatment of COPD.
Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K. neil.press@novartis.com
Neil J
NJ
Press
Roger J
RJ
Taylor
Joseph D
JD
Fullerton
Pamela
P
Tranter
Clive
C
McCarthy
Thomas H
TH
Keller
Nicola
N
Arnold
David
D
Beer
Lyndon
L
Brown
Robert
R
Cheung
Julie
J
Christie
Alastair
A
Denholm
Sandra
S
Haberthuer
Julia D I
JD
Hatto
Mark
M
Keenan
Mark K
MK
Mercer
Helen
H
Oakman
Helene
H
Sahri
Andrew R
AR
Tuffnell
Morris
M
Tweed
John W
JW
Tyler
Trixie
T
Wagner
John R
JR
Fozard
Alexandre
A
Trifilieff
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D012995:Solubility; D014839:Vomiting / Q000188:drug therapy
D058988:Phosphodiesterase 4 Inhibitors