Pyrazolopyridines as a novel structural class of potent and selective PDE4 inhibitors.
Optimisation of a high-throughput screening hit resulted in the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective inhibitors of Phosphodiesterase 4 (PDE4). Herein, we describe early SAR studies around this novel template highlighting preferred substituents and rationalization of SAR through X-ray crystal structures of analogues bound to the PDE4 active site. Pyrazolopyridine 20a was found to be a potent and selective PDE4 inhibitor which also inhibits LPS induced TNF-alpha production from isolated human peripheral blood mononuclear cells and has an encouraging rat PK profile suitable for oral dosing.
GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. nicole.j.hamblin@gsk.com
J Nicole
JN
Hamblin
Tony D R
TD
Angell
Stuart P
SP
Ballantine
Caroline M
CM
Cook
Anthony W J
AW
Cooper
John
J
Dawson
Christopher J
CJ
Delves
Paul S
PS
Jones
Mika
M
Lindvall
Fiona S
FS
Lucas
Charlotte J
CJ
Mitchell
Margarete Y
MY
Neu
Lisa E
LE
Ranshaw
Yemisi E
YE
Solanke
Don O
DO
Somers
Joanne O
JO
Wiseman
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry*; D003521:Cyclopropanes / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D008954:Models, Biological; D008956:Models, Chemical; D058988:Phosphodiesterase 4 Inhibitors; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D011760:Pyrrolidinones / Q000737:chemistry; D051381:Rats; D020889:Rolipram / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D058988:Phosphodiesterase 4 Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011760:Pyrrolidinones; D014409:Tumor Necrosis Factor-alpha; C118531:pyrazolopyridine; C424423:Roflumilast; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram