Discovery of a novel class of phosphodiesterase 10A inhibitors and identification of clinical candidate 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the treatment of schizophrenia.
By utilizing structure-based drug design (SBDD) knowledge, a novel class of phosphodiesterase (PDE) 10A inhibitors was identified. The structure-based drug design efforts identified a unique "selectivity pocket" for PDE10A inhibitors, and interactions within this pocket allowed the design of highly selective and potent PDE10A inhibitors. Further optimization of brain penetration and drug-like properties led to the discovery of 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920). This PDE10A inhibitor is the first reported clinical entry for this mechanism in the treatment of schizophrenia.
Verhoest
Patrick R
PR
Neuroscience, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. patrick.r.verhoest@pfizer.com
Chapin
Douglas S
DS
Corman
Michael
M
Fonseca
Kari
K
Harms
John F
JF
Hou
Xinjun
X
Marr
Eric S
ES
Menniti
Frank S
FS
Nelson
Frederick
F
O'Connor
Rebecca
R
Pandit
Jayvardhan
J
Proulx-Lafrance
Caroline
C
Schmidt
Anne W
AW
Schmidt
Christopher J
CJ
Suiciak
Judith A
JA
Liras
Spiros
S
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D018360:Crystallography, X-Ray; D004285:Dogs; D005260:Female; D006801:Humans; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000188:drug therapy*; D013329:Structure-Activity Relationship
C545121:2-((4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy)methyl)quinoline; D014150:Antipsychotic Agents; D011720:Pyrazoles; D011804:Quinolines; C512064:PDE10A protein, rat; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases