8oeg

PDE4B bound to MAPI compound 92aPDE4B bound to MAPI compound 92a

Structural highlights

8oeg is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.89Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PDE4B_HUMAN Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents.^[1] ^[2]

Publication Abstract from PubMed

In this paper, we report the discovery of dual M(3) antagonist-PDE4 inhibitor (MAPI) compounds for the inhaled treatment of pulmonary diseases. The identification of dual compounds was enabled by the intuition that the fusion of a PDE4 scaffold derived from our CHF-6001 series with a muscarinic scaffold through a common linking ring could generate compounds active versus both the transmembrane M(3) receptor and the intracellular PDE4 enzyme. Two chemical series characterized by two different muscarinic scaffolds were investigated. SAR optimization was aimed at obtaining M(3) nanomolar affinity coupled with nanomolar PDE4 inhibition, which translated into anti-bronchospastic efficacy ex vivo (inhibition of rat trachea contraction) and into anti-inflammatory efficacy in vitro (inhibition of TNFalpha release). Among the best compounds, compound 92a achieved the goal of demonstrating in vivo efficacy and duration of action in both the bronchoconstriction and inflammation assays in rat after intratracheal administration.

Discovery of M(3) Antagonist-PDE4 Inhibitor Dual Pharmacology Molecules for the Treatment of Chronic Obstructive Pulmonary Disease.,Armani E, Rizzi A, Capaldi C, De Fanti R, Delcanale M, Villetti G, Marchini G, Pisano AR, Pitozzi V, Pittelli MG, Trevisani M, Salvadori M, Cenacchi V, Puccini P, Amadei F, Pappani A, Civelli M, Patacchini R, Baker-Glenn CAG, Van de Poel H, Blackaby WP, Nash K, Amari G J Med Chem. 2021 Jul 8;64(13):9100-9119. doi: 10.1021/acs.jmedchem.1c00204. Epub , 2021 Jun 18. PMID:34142835^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Xu RX, Hassell AM, Vanderwall D, Lambert MH, Holmes WD, Luther MA, Rocque WJ, Milburn MV, Zhao Y, Ke H, Nolte RT. Atomic structure of PDE4: insights into phosphodiesterase mechanism and specificity. Science. 2000 Jun 9;288(5472):1822-5. PMID:10846163
↑ Xu RX, Rocque WJ, Lambert MH, Vanderwall DE, Luther MA, Nolte RT. Crystal structures of the catalytic domain of phosphodiesterase 4B complexed with AMP, 8-Br-AMP, and rolipram. J Mol Biol. 2004 Mar 19;337(2):355-65. PMID:15003452 doi:http://dx.doi.org/10.1016/j.jmb.2004.01.040
↑ Armani E, Rizzi A, Capaldi C, De Fanti R, Delcanale M, Villetti G, Marchini G, Pisano AR, Pitozzi V, Pittelli MG, Trevisani M, Salvadori M, Cenacchi V, Puccini P, Amadei F, Pappani A, Civelli M, Patacchini R, Baker-Glenn CAG, Van de Poël H, Blackaby WP, Nash K, Amari G. Discovery of M(3) Antagonist-PDE4 Inhibitor Dual Pharmacology Molecules for the Treatment of Chronic Obstructive Pulmonary Disease. J Med Chem. 2021 Jul 8;64(13):9100-9119. PMID:34142835 doi:10.1021/acs.jmedchem.1c00204

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OCA

[1] Xu RX, Hassell AM, Vanderwall D, Lambert MH, Holmes WD, Luther MA, Rocque WJ, Milburn MV, Zhao Y, Ke H, Nolte RT. Atomic structure of PDE4: insights into phosphodiesterase mechanism and specificity. Science. 2000 Jun 9;288(5472):1822-5. PMID:10846163

[2] Xu RX, Rocque WJ, Lambert MH, Vanderwall DE, Luther MA, Nolte RT. Crystal structures of the catalytic domain of phosphodiesterase 4B complexed with AMP, 8-Br-AMP, and rolipram. J Mol Biol. 2004 Mar 19;337(2):355-65. PMID:15003452 doi:http://dx.doi.org/10.1016/j.jmb.2004.01.040

[3] Armani E, Rizzi A, Capaldi C, De Fanti R, Delcanale M, Villetti G, Marchini G, Pisano AR, Pitozzi V, Pittelli MG, Trevisani M, Salvadori M, Cenacchi V, Puccini P, Amadei F, Pappani A, Civelli M, Patacchini R, Baker-Glenn CAG, Van de Poël H, Blackaby WP, Nash K, Amari G. Discovery of M(3) Antagonist-PDE4 Inhibitor Dual Pharmacology Molecules for the Treatment of Chronic Obstructive Pulmonary Disease. J Med Chem. 2021 Jul 8;64(13):9100-9119. PMID:34142835 doi:10.1021/acs.jmedchem.1c00204

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