Discovery and Optimization of 4-(8-(3-Fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic Acid, an Improved PDE4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease (COPD).
Herein we describe the optimization of a series of PDE4 inhibitors, with special focus on solubility and pharamcokinetics, to clinical compound 2, 4-(8-(3-fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic acid. Although compound 2 produces emesis in humans when given as a single dose, its exemplary pharmacokinetic properties enabled a novel dosing regime comprising multiple escalating doses and the resultant achievement of high plasma drug levels without associated nausea or emesis.
Novartis Institutes for Biomedical Research , Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
Neil J
NJ
Press
Novartis Institutes for Biomedical Research , Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
Roger J
RJ
Taylor
Novartis Institutes for Biomedical Research , Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
Joseph D
JD
Fullerton
Novartis Institutes for Biomedical Research , Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
Pamela
P
Tranter
Novartis Institutes for Biomedical Research , Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
Clive
C
McCarthy
Novartis Institutes for Biomedical Research , Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
Thomas H
TH
Keller
Novartis Institutes for Biomedical Research , Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
Nicola
N
Arnold
Novartis Institutes for Biomedical Research , Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
David
D
Beer
Novartis Institutes for Biomedical Research , Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
Lyndon
L
Brown
Novartis Institutes for Biomedical Research , Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
Robert
R
Cheung
Novartis Institutes for Biomedical Research , Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
Julie
J
Christie
Novartis Institutes for Biomedical Research , Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
Alastair
A
Denholm
Novartis Institutes for Biomedical Research , Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
Sandra
S
Haberthuer
Novartis Institutes for Biomedical Research , Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
Julia D I
JD
Hatto
Novartis Institutes for Biomedical Research , Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
Mark
M
Keenan
Novartis Institutes for Biomedical Research , Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
Mark K
MK
Mercer
Novartis Institutes for Biomedical Research , Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
Helen
H
Oakman
Novartis Institutes for Biomedical Research , Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
Helene
H
Sahri
Novartis Institutes for Biomedical Research , Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
Andrew R
AR
Tuffnell
Novartis Institutes for Biomedical Research , Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
Morris
M
Tweed
Novartis Institutes for Biomedical Research , Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
Alexandre
A
Trifilieff
D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009287:Naphthyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D009325:Nausea / Q000139:chemically induced; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014839:Vomiting / Q000139:chemically induced
C000603344:4-(8-(3-fluorophenyl)-1,7-naphthyridin-6-yl)cyclohexanecarboxylic acid; D003509:Cyclohexanecarboxylic Acids; D009287:Naphthyridines; D058988:Phosphodiesterase 4 Inhibitors