Discovery of 2-(cyclopentylamino)thieno[3,2-d]pyrimidin-4(3H)-one derivatives as a new series of potent phosphodiesterase 7 inhibitors.
The discovery of a new series of potent phosphodiesterase 7 (PDE7) inhibitors is described. Novel thieno[3,2-d]pyrimidin-4(3H)-one hit compounds were identified from our chemical library. Preliminary modifications of the hit compounds were performed, resulting in the discovery of a fragment-sized compound (10) with highly improved ligand efficiency. Compound design was guided by structure-activity relationships and computational modeling. The 6-substituted derivatives of the thienopyrimidinone showed diminished activity and enzyme selectivity. However, synthesis of the 7-substituted derivatives resulted in the discovery of 28e, a desirable lead compound that selectively inhibits PDE7 with single-digit nanomolar potency while displaying potent cellular efficacy.
Drug Research Center, Kaken Pharmaceutical Co. Ltd. , 14 Shinomiya Minamigawara-cho, Yamashina, Kyoto 607-8042, Japan.
Kentaro
K
Kawai
Yusuke
Y
Endo
Takeshi
T
Asano
Seiji
S
Amano
Keisuke
K
Sawada
Noriko
N
Ueo
Nobuaki
N
Takahashi
Yo
Y
Sonoda
Mika
M
Nagai
Noriyuki
N
Kamei
Naoya
N
Nagata
D000818:Animals; D003198:Computer Simulation; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
C000595386:2-(cyclopentylamino)-3-ethyl-7-pyridin-3-ylthieno(3,2-d)pyrimidin-4(3H)-one; D010726:Phosphodiesterase Inhibitors; D011744:Pyrimidinones; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7