Palladium-catalyzed cross-coupling reactions for the synthesis of 6, 8-disubstituted 1,7-naphthyridines: a novel class of potent and selective phosphodiesterase type 4D inhibitors.

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Hersperger R, Bray-French K, Mazzoni L, Muller T

Palladium-catalyzed cross-coupling reactions for the synthesis of 6, 8-disubstituted 1,7-naphthyridines: a novel class of potent and selective phosphodiesterase type 4D inhibitors.

J Med Chem. 2000 Feb 24;43(4):675-82.

PubMed ID

10691693 [ View in PubMed

]

Abstract

Recently, four subtypes of the human phosphodiesterase type 4 (PDE4A-D) enzyme have been described. So far, only very few PDE4 subtype-selective inhibitors are known. Herein, we describe the synthesis of 6,8-disubstituted 1,7-naphthyridines and their characterization as potent and selective inhibitors of PDE4D which suppress the oxidative burst in human eosinophils with IC(50) values as low as 0.7 nM. SAR development and the extended use of palladium-catalyzed cross-coupling reactions led to compound 11 which inhibited human PDE4D with an IC(50) value of 1 nM. Thus, compound 11 was 55, 175, and 1000 times more potent in inhibiting PDE4D over PDE4B, PDE4A, and PDE4C. In a Brown Norway rat model of allergic asthma, compound 11 when given by the oral route (1 mg/kg) reduced by more than 50% the influx of eosinophils, T-cells, and neutrophils into bronchoalveolar lavage fluid (BALF) samples obtained from antigen-challenged animals. Thus, PDE4D-selective inhibitors of the 1,7-naphthyridine class have the potential as an oral therapy for treating asthma.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
(R)-Rolipram	cAMP-specific 3',5'-cyclic phosphodiesterase 4D	IC 50 (nM)	390	N/A	N/A	Details
4-[8-(3-nitrophenyl)-1,7-naphthyridin-6-yl]benzoic acid	cAMP-specific 3',5'-cyclic phosphodiesterase 4A	IC 50 (nM)	88	N/A	N/A	Details
4-[8-(3-nitrophenyl)-1,7-naphthyridin-6-yl]benzoic acid	cAMP-specific 3',5'-cyclic phosphodiesterase 4D	IC 50 (nM)	1	N/A	N/A	Details