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

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.

Pharmacological Profile of a Novel Phosphodiesterase 4 Inhibitor, 4-(8-Benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridin-6-yl)-benzoic Acid (NVP-ABE171), a 1,7-Naphthyridine Derivative, with Anti-Inflammatory Activities

“…PDE4D was mainly expressed in eosinophils and to a lesser extent in neutrophils. Based on all this information, we designed PDE4 inhibitors displaying different selectivity profiles against the PDE4 isozymes (Hersperger et al, 2000) and as a result of this strategy, NVP-ABE171, a selective inhibitor for PDE4B and 4D, was selected for further profiling.…”

“…PDE2 was obtained as the peak of activity by using 100 M cAMP and PDE5 as a peak of activity by using 100 M cGMP. Purification of human PDE3 and cloning and expression of human PDE4A, 4C, 4D, and rat PDE4B were performed as previously described (Hersperger et al, 2000). Pooled active fractions of each enzyme were made in ethylene glycol and stored at Ϫ20°C.…”

“…Our research efforts in finding novel PDE4 inhibitors were based upon a new approach. We wanted to find orally active, second-generation PDE4 inhibitors displaying different selectivity profiles against the PDE4 isozymes (Hersperger et al, 2000). In this report we investigate the in vitro and in vivo antiinflammatory properties of 4-(8-benzo[1,2,5]oxadiazol-5-yl- [1,7]naphthyridin-6-yl)-benzoic acid (NVP-ABE171), an inhibitor for the PDE4B and 4D isozymes.…”

A general synthesis of 8‐hydroxy‐6‐substituted‐1,7‐naphthyridines

“…The discovery of 1,7-naphthyridines as a novel class of potent phosphodiesterase type 4 inhibitors [1] created much interest in finding facile methods for preparing these compounds. As the interest in this class of heterocycles is rather new, not many methods are described in the literature.…”

“…As the interest in this class of heterocycles is rather new, not many methods are described in the literature. One of the methods [1] started from 3-pyridylacetonitrile-N-oxide employing trimethylsilylcyanide and diethylcarbamyl chloride as reagents (Scheme 1) to make the desired compounds. The workup is tedious and the yields are low.…”