Alkyl-bridged substituted 8-arylquinolines as highly potent PDE IV inhibitors (original) (raw)
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Journal of Medicinal Chemistry, 2014
The first steps in the selection process of a new anti-inflammatory drug for the inhaled treatment of asthma and chronic obstructive pulmonary disease are herein described. A series of novel ester derivatives of 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl) ethanol have been synthesized and evaluated for inhibitory activity toward cAMP-specific phosphodiesterase-4 (PDE4). In particular, esters of variously substituted benzoic acids were extensively explored, and structural modification of the alcoholic and benzoic moieties were performed to maximize the inhibitory potency. Several compounds with high activity in cell-free and cell-based assays were obtained. Through the evaluation of opportune in vitro ADME properties, a potential candidate suitable for inhaled administration in respiratory diseases was identified and tested in an in vivo model of pulmonary inflammation, proving its efficacy.
Bioorganic & Medicinal Chemistry Letters, 2018
We describe the design, synthesis and evaluation of a series of N 2 ,N 4-diaminoquinazoline analogs as PDE5 inhibitors. Twenty compounds were prepared and these were assessed in terms of their PDE5 and PDE6 activity, ex-vivo vasodilation response, mammalian cytotoxicity and aqueous solubility. Molecular docking was used to determine the binding mode of the series and this was demonstrated to be consistent with the observed SAR. Compound 15 was the most active PDE5 inhibitor (IC 50 = 0.072 ± 0.008 µM) and exhibited 4.6-fold selectivity over PDE6. Ex-vivo assessment of 15 and 22 in a rat pulmonary artery vasodilation model demonstrated EC 50 s of 1.63 ± 0.72 µM and 2.28 ± 0.74 µM respectively.
Design, synthesis, and biological evaluation of 8-biarylquinolines: A novel class of PDE4 inhibitors
Bioorganic & Medicinal Chemistry Letters, 2008
Growing evidence suggests that matrix metalloproteinases (MMP) are involved in thrombus dissolution; then, considering that new therapeutic strategies are required for controlling hemorrhage, we hypothesized that MMP inhibition may reduce bleeding by delaying fibrinolysis. Thus, we designed and synthesized a novel series of MMP inhibitors to identify potential candidates for acute treatment of bleeding. Structure-based and knowledge-based strategies were utilized to design this novel chemical series, α-spiropiperidine hydroxamates, of potent and soluble (>75 µg/mL) pan-MMP inhibitors. The initial hit, 12, was progressed to an optimal lead 19d. Racemic 19d showed a remarkable in vitro phenotypic response and outstanding in vivo efficacy; in fact, the mouse bleeding time at 1 mg/kg was 0.85 min compared to 29.28 min using saline. In addition, 19d displayed an optimal ADME and safety profile (e.g., no thrombus formation). Its corresponding enantiomers were separated, leading to the preclinical candidate 5 (described in drug annotations series, ref18).
Quinazolines: Combined type 3 and 4 phosphodiesterase inhibitors
Bioorganic & Medicinal Chemistry Letters, 1998
A series of quinazolines has been prepared and evaluated for its ability to inhibit cyclic AMP phosphodiesterase type 3, type 4A, 4B and 4D. The most potent inhibitors showed IC50 values in the nanomolar range for type 3 and type 4 isoforms and bind with high affinity to the [3H]rolipram binding site. These quinazolines represent a new family of potent mixed PDE 3 / 4 inhibitors and are expected to have a therapeutic potential. 0 1998 Elsevier Science Ltd. All rights reserved. Isozyme selective phosphodiesterase (PDE) inhibitors may represent a new class of drugs for the treatment of obstructive pulmonary disease (e.g. asthma). PDE 3 inhibitors, and possibly PDE 4 inhibitors possess bronchodilator activity. On the other hand, synthesis and release of inflammatory mediators, chemotaxis and proliferation of inflammatory cells in response to antigen challenge are inhibited by agents that produce an increase in the intracellular concentration of cAMp.I3 Increase of cAMP level can be achieved by inhibition of cAMP PDE [3':5'-nucleotidohydrolase, EC 3.1.4.17]. Since the different isoenzymes, that preferentially hydrolyse cAMP, are not uniformly distributed in different cell types, 4'5 they are sensitive to selective inhibitors and are interesting drug targets for a variety of different diseases. The quest of novel antiinflammatory agents has led chemists and pharmacologists to focus on selective inhibitors of PDE 4 because it is the predominant form in human leukocytes. 13'5'6 The recent discovery of different cDNA isoforms and splice variants of PDE 4 suggests that the regulation of cAMP metabolism in leukocytes may be more complex than originally thought. Four distinct human isoforms, provisionally designated PDE 4A, 4B, 4C, 4D, 5 have been cloned and expressed. 7-1~ An increase in intracellular cAMP induces the synthesis of the A, B, and D isoforms, 6'12 suggesting a role for these enzymes in the long term regulation of cAMP metabolism. Mixed PDE 3 / 4 inhibitors may combine, therefore, both bronchodilator and antiinflammatory properties. Zardaverine [6-1 Fax
Journal of medicinal chemistry, 2017
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 h...
Bioorganic & Medicinal Chemistry Letters, 2002
The discovery, synthesis and biological activity of a series of triarylethane phosphodiesterase 4 inhibitors is described. Structure-activity relationship studies are presented for CDP840 (29), a potent, chiral, selective inhibitor of PDE 4 (IC 50 4 nM). CDP840 is non-emetic in the ferret at 30 mg kg À1 (po), active in models of inflammation and reverses ozone-induced bronchial hyperreactivity in the guinea pig. #