8OEG
PDE4B bound to MAPI compound 92a
Summary for 8OEG
| Entry DOI | 10.2210/pdb8oeg/pdb |
| Descriptor | cAMP-specific 3',5'-cyclic phosphodiesterase 4B, ZINC ION, MAGNESIUM ION, ... (5 entities in total) |
| Functional Keywords | human phosphodiesterase 4b, mapi compound, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 49260.09 |
| Authors | Rizzi, A.,Armani, E. (deposition date: 2023-03-10, release date: 2023-04-26, Last modification date: 2023-11-08) |
| Primary citation | 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 Cited by 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: 37561958DOI: 10.1021/acs.jmedchem.3c01012 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.89 Å) |
Structure validation
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