5OHJ
Human phosphodiesterase 4B catalytic domain in complex with a pyrrolidinyl inhibitor.
Summary for 5OHJ
| Entry DOI | 10.2210/pdb5ohj/pdb |
| Descriptor | cAMP-specific 3',5'-cyclic phosphodiesterase 4B, ZINC ION, MAGNESIUM ION, ... (5 entities in total) |
| Functional Keywords | human phosphodiesterase 4b, hydrolase, pyrrolidinyl inhibitor, pde4b |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 98524.02 |
| Authors | Rizzi, A.,Carzaniga, L.,Armani, E. (deposition date: 2017-07-17, release date: 2017-12-13, Last modification date: 2024-05-01) |
| Primary citation | Carzaniga, L.,Amari, G.,Rizzi, A.,Capaldi, C.,De Fanti, R.,Ghidini, E.,Villetti, G.,Carnini, C.,Moretto, N.,Facchinetti, F.,Caruso, P.,Marchini, G.,Battipaglia, L.,Patacchini, R.,Cenacchi, V.,Volta, R.,Amadei, F.,Pappani, A.,Capacchi, S.,Bagnacani, V.,Delcanale, M.,Puccini, P.,Catinella, S.,Civelli, M.,Armani, E. Discovery and Optimization of Thiazolidinyl and Pyrrolidinyl Derivatives as Inhaled PDE4 Inhibitors for Respiratory Diseases. J. Med. Chem., 60:10026-10046, 2017 Cited by PubMed Abstract: Phosphodiesterase 4 (PDE4) is a key cAMP-metabolizing enzyme involved in the pathogenesis of inflammatory disease, and its pharmacological inhibition has been shown to exert therapeutic efficacy in chronic obstructive pulmonary disease (COPD). Herein, we describe a drug discovery program aiming at the identification of novel classes of potent PDE4 inhibitors suitable for pulmonary administration. Starting from a previous series of benzoic acid esters, we explored the chemical space in the solvent-exposed region of the enzyme catalytic binding pocket. Extensive structural modifications led to the discovery of a number of heterocycloalkyl esters as potent in vitro PDE4 inhibitors. (S*,S**)-18e and (S*,S**)-22e, in particular, exhibited optimal in vitro ADME and pharmacokinetics properties and dose-dependently counteracted acute lung eosinophilia in an experimental animal model. The optimal biological profile as well as the excellent solid-state properties suggest that both compounds have the potential to be effective topical agents for treating respiratory inflammatory diseases. PubMed: 29200281DOI: 10.1021/acs.jmedchem.7b01044 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.6 Å) |
Structure validation
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