8OEG

PDE4B bound to MAPI compound 92a

8OEG の概要

• エントリーDOI: 10.2210/pdb8oeg/pdb
• 分子名称: cAMP-specific 3',5'-cyclic phosphodiesterase 4B, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: human phosphodiesterase 4b, mapi compound, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 49260.09

構造登録者

Rizzi, A.,Armani, E. (登録日: 2023-03-10, 公開日: 2023-04-26, 最終更新日: 2023-11-08)

主引用文献

Rizzi, A.,Amari, G.,Pivetti, F.,Delcanale, M.,Amadei, F.,Pappani, A.,Fornasari, L.,Villetti, G.,Marchini, G.,Pisano, A.R.,Pitozzi, V.,Pittelli, M.G.,Trevisani, M.,Salvadori, M.,Cenacchi, V.,Fioni, A.,Puccini, P.,Civelli, M.,Patacchini, R.,Baker-Glenn, C.,Van de Poel, H.,Blackaby, W.,Nash, K.,Armani, E.
Optimization of M 3 Antagonist-PDE4 Inhibitor (MAPI) Dual Pharmacology Molecules for the Treatment of COPD.
J.Med.Chem., 66:11476-11497, 2023

PubMed Abstract: Aiming at the inhaled treatment of pulmonary diseases, the optimization process of the previously reported MAPI compound is herein described. The project was focused on overcoming the chemical stability issue and achieving a balanced bronchodilator/anti-inflammatory profile in rats in order to be confident in a clinical effect without having to overdose at one of the biological targets. The chemical strategy was based on fine-tuning of the substitution pattern in the muscarinic and PDE4 structural portions of the dual pharmacology compounds, also making use of the analysis of a proprietary crystal structure in the PDE4 catalytic site. Compound was identified as a chemically stable, potent, and balanced MAPI lead compound, as assessed in bronchoconstriction and inflammation assays in rats after intratracheal administration. After the in-depth investigation of the pharmacological and solid-state profile, proved to be safe and suitable for development.

PubMed: 37561958
DOI: 10.1021/acs.jmedchem.3c01012

実験手法

X-RAY DIFFRACTION (1.89 Å)