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.
Hamblin
J Nicole
JN
GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. nicole.j.hamblin@gsk.com
Angell
Tony D R
TD
Ballantine
Stuart P
SP
Cook
Caroline M
CM
Cooper
Anthony W J
AW
Dawson
John
J
Delves
Christopher J
CJ
Jones
Paul S
PS
Lindvall
Mika
M
Lucas
Fiona S
FS
Mitchell
Charlotte J
CJ
Neu
Margarete Y
MY
Ranshaw
Lisa E
LE
Solanke
Yemisi E
YE
Somers
Don O
DO
Wiseman
Joanne O
JO
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