Discovery of 2‑(Cyclopentylamino)thieno[3,2‑d]pyrimidin-4(3H)‑one Derivatives as a New Series of Potent Phosphodiesterase 7 Inhibitors

• Published in: Journal of medicinal chemistry Vol. 57; no. 23; pp. 9844 - 9854
• Main Authors: Kawai, Kentaro, Endo, Yusuke, Asano, Takeshi, Amano, Seiji, Sawada, Keisuke, Ueo, Noriko, Takahashi, Nobuaki, Sonoda, Yo, Nagai, Mika, Kamei, Noriyuki, Nagata, Naoya
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.12.2014; Amer Chemical Soc
• Subjects: Animals; Chemistry, Medicinal; Computer Simulation; Cyclic Nucleotide Phosphodiesterases, Type 7 - antagonists & inhibitors; Humans; Life Sciences & Biomedicine; Mice; Pharmacology & Pharmacy; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - pharmacology; Pyrimidinones - chemical synthesis; Pyrimidinones - pharmacology; Science & Technology; Structure-Activity Relationship; STRUCTURAL CLASS; IN-VIVO; DISEASE; SELECTIVE PDE7 INHIBITORS; PART 1; LIGAND; EFFICIENCY; COPD
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm5008215

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.