Discovery of a Phosphodiesterase 7A Inhibitor of High Isozyme Selectivity Exhibiting In Vivo Anti-Osteoporotic Effects

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-12-26 DOI:10.1021/acsmedchemlett.4c0057010.1021/acsmedchemlett.4c00570

Kentaro Kondo, Kazuki Otake, Tetsudo Kaya, Shohei Miwa, Yoshifumi Ueyama, Tsunemitsu Haruta, Jun Nishihata, Takashi Nakagawa, Nobuhide Azuma, Kayoko Takagi, Toshiki Urashima, Yuki Kitao and Makoto Shiozaki*,

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Abstract

Phosphodiesterases (PDEs) have drawn attention due to their critical roles in physiological and pathological conditions. Many research groups have studied these hydrolytic enzymes to develop new drugs, including apremilast as a PDE4 inhibitor and sildenafil as a PDE5 inhibitor. Targeting PDE7 has also been deemed a rational strategy to ameliorate autoimmune conditions. However, to date, no successful clinical results have been reported. We postulated that progress in these studies with PDE7 had been hampered by the lack of a potent ligand with a reasonable selectivity for this PDE isozyme. Therefore, starting from a PDE7A/7B dual inhibitor, our investigations led to improved selectivity along with extended metabolic stability, resulting in a novel PDE7A inhibitor 26. This compound with high selectivity over the closest isozyme is an ideal chemical entity to unveil new pharmacological roles of PDE7A-dependent signaling, as exemplified by the in vivo antiosteoporotic effects.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.