Discovery and SAR study of 2-(4-pyridylamino)thieno[3,2-d]pyrimidin-4(3H)-ones as soluble and highly potent PDE7 inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 25; no. 3; pp. 649 - 653
• Main Authors: Endo, Yusuke, Kawai, Kentaro, Asano, Takeshi, Amano, Seiji, Asanuma, Yoshihito, Sawada, Keisuke, Ogura, Keiji, Nagata, Naoya, Ueo, Noriko, Takahashi, Nobuaki, Sonoda, Yo, Kamei, Noriyuki
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.02.2015; Elsevier
• Subjects: Aqueous solubility; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Cyclic Nucleotide Phosphodiesterases, Type 7 - antagonists & inhibitors; Cyclic Nucleotide Phosphodiesterases, Type 7 - metabolism; Drug Evaluation, Preclinical; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Phosphodiesterase; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - metabolism; Physical Sciences; Protein Binding; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - metabolism; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - metabolism; Science & Technology; Solubility; Structure-Activity Relationship; T-cell; Thienopyrimidinone; T-cell; Thienopyrimidinone; Aqueous solubility; Phosphodiesterase; STRUCTURAL CLASS; ANALOGS; DRUG DISCOVERY; DISEASE; PART 1; EFFICIENCY; CAMP
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.11.090

[Display omitted] The discovery and SAR study of a new series of soluble and highly potent phosphodiesterase (PDE) 7 inhibitors are described herein. We explored a new lead compound with improved solubility, which led to the discovery of a 2-(4-pyridylamino)thieno[3,2-d]pyrimidin-4(3H)-one series. The introduction of 3-piperidines at the 7-position resulted in the significant enhancement of PDE7 activity. In particular, compound 32 also showed strong PDE7 inhibitory activity; good selectivity against PDE3, 4, and 5; and good aqueous solubility.