Phosphodiesterase inhibitors. Part 3: Design, synthesis and structure–activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-dihydropyridazinones with anti-inflammatory and bronchodilatory activity

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Abstract

(−)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. A survey of potential bicyclic heteroaromatic replacement subunits for the pyrazolo[1,5-a]pyridine core of KCA-1490 has identified the 4-methoxy-2-(trifluoromethyl)benzo[d]thiazol-7-yl and 8-methoxy-2-(trifluoromethyl)quinolin-5-yl analogues as dual PDE3/4-inhibitory compounds that potently suppress histamine-induced bronchoconstriction and exhibit anti-inflammatory activity in vivo.

Introduction

Therapeutic management of asthma and chronic obstructive pulmonary disease (COPD) varies according to the severity of the symptoms, but for many years corticosteroids and β2-agonists have been the mainstay of treatment regimens.1 Steroids provide control of underlying inflammatory dysfunction, whilst the bronchodilatory activity of β2-agonists primarily serves to afford symptomatic relief for airway constriction. In recent years combination treatments comprising an inhaled corticosteroid (ICS) and long-acting β2-agonist (LABA) have been actively developed, and these allow effective management of the majority of mild-to-moderate asthma.1 However, long-term use of corticosteroids in high doses can produce several adverse side effects, driving an on-going search for steroid-sparing treatment options.2 Moreover, the safety of LABAs has also recently come under scrutiny, with the US Food and Drug Administration ordering a series of post-approval clinical trials from 2011 to evaluate their potential involvement in serious adverse outcomes among asthma patients.3

One important avenue explored as a new therapeutic option for respiratory disease has focused on the development of inhibitors for the phosphodiesterase (PDE) 4 enzyme family, and this has culminated in the deployment of roflumilast (Fig. 1), which, as the first PDE4-selective inhibitor to gain regulatory approval, has recently been launched for the treatment of severe COPD.4 The potential utility of PDE4 inhibitors for treatment of respiratory disease derives from their pronounced anti-inflammatory activity, but they also exhibit modest activity for inducing relaxation of airway smooth muscle tissue.5 However, PDE3 inhibitors are known to be superior to PDE4 inhibitors in mediating relaxation of airway smooth muscle.6 Thus, either the combination of PDE3 and PDE4 inhibitors or the use of dual PDE3/4 inhibitors may offer enhanced therapeutic potential for asthma and COPD compared to treatment with individual PDE family selective agents alone, and this notion is supported by reports that combined inhibition of PDE3 and PDE4 may function additively or synergistically to induce airway smooth muscle relaxation.7

In the search for an alternative approach to the ICS/LABA regimen for asthma and COPD management, we have also evaluated and found promising activity with dual PDE3/4-inhibitory compounds. Thus, we have previously disclosed (−)-6-[7-methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (KCA-1490, Fig. 1) as a dual PDE3/4 inhibitor with very potent combined bronchodilatory and anti-inflammatory activity and an improved therapeutic window over roflumilast in a number of in vitro and in vivo models used for pharmacological profiling.8 Our structure–activity relationship studies with compound series related to KCA-1490 revealed that the PDE3-inhibitory activity is heavily dependent on the presence of the 5-methyldihydropyridazinone, a subunit that is strongly represented in established PDE3 inhibitors,9, 10 and we have rationalized this dependence in our previously reported8b binding models (summarized here in Fig. 2). The N(1) nitrogen center and the oxygen atom of the 7-methoxypyrazolo[1,5-a]pyridine core subunit proved to be critical determinants for potent PDE4 inhibition, and these centers correspond to the catechol ether oxygen atoms of roflumilast (Fig. 1) in the role that they play in engaging the purine-scanning glutamine of the PDE4 catalytic pocket (Fig. 2B).8b Evaluation of a series of substituents at the pyrazolopyridine 2-position revealed that a trifluoromethyl group conferred an efficacious balance of PDE3 and PDE4 inhibition and was optimal for activity in our pharmacological models.8a Having defined the essential structural features required for dual PDE3/4-inhibitory activity within the confines of our pyrazolo[1,5-a]pyridine-based series, there remained considerable scope for structural variation with isosteric replacements for the core bicycle. We therefore set out to evaluate a series of KCA-1490 analogues with alternative fused 5–6 bicyclic heteroaromatics in place of the pyrazolo[1,5-a]pyridine (18, Fig. 1) together with the ring expanded analogue, quinoline 9. The synthesis and activity of these compounds is presented here.

Section snippets

Chemistry

Synthesis of triazolopyridine 1 commenced with the formation of N-aminopyridinium salt 11 by treatment of parent pyridine 10 with O-mesitylenesulfonylhydroxylamine (MSH) (Scheme 1). Construction of the 2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine bicycle was then accomplished by condensation of salt 11 with TFAA to afford 12 in moderate yield. DIBAL-H reduction of the ester followed by TBS protection of the intermediate primary alcohol gave 13. Iodination at the 5-position of the

Results and discussion

Having previously identified8a (−)-6-[7-methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (KCA-1490) as a dual PDE3/4 inhibitor that exhibited potent combined bronchodilatory and anti-inflammatory activity, we set out to evaluate a range of related compounds (19) in which the pyrazolo[1,5-a]pyridine subunit of the parent structure was replaced by an alternative heterobicycle. For the majority of compounds in the target set we chose to replace the

Conclusions

In this study we have surveyed the potential of several heterobicycles as replacement subunits for the pyrazolo[1,5-a]pyridine core of our dual PDE3/4 inhibitor, KCA-1490. Our initial evaluation has been undertaken with the compounds in racemic form, although their PDE3-inhibitory activity is likely associated primarily with only one of the two enantiomers. Thus in our previous work with the parent pyrazolopyridine8 the (−)-enantiomer (KCA-1490), to which the pharmacological activity is

General

1H NMR spectra were measured with a JEOL JNM-ECA-400 or -ECX-400 (400 MHz) spectrometer. The chemical shifts are expressed in parts per million (δ value) downfield from tetramethylsilane, using tetramethylsilane (δ = 0) and/or residual solvents such as chloroform (δ = 7.26) as an internal standard. Splitting patterns are indicated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet. Measurements of mass spectra were performed with a JEOL JMS-SX102X mass spectrometer.

Acknowledgments

We are grateful to Dr S. J. MacKenzie, Dr S. Hastings and Dr R. A. Clayton of the Kyorin Scotland Research Laboratory for their many valuable suggestions and performing the PDE inhibition assays. PyMOL from W.L. DeLano, DeLano Scientific, was used to create the protein structure images in this work.

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      As observed, even an addition of a small substituent such as a methyl was deleterious for the activity (compound 77) (Fig. 24). In the subsequent works, exploration of bioisosteric replacements gave compound 78, the first quinoline with PDE3 and PDE4 inhibitory effect [119], while bioisosteric change for imidazopyridine and ring contraction of pyridazinone led to compound 79 [120]. Vesnarinone (82) is a selective PDE3 inhibitor with moderate activity (PDE3A IC50 = 10.7 μM; PDE3B IC50 = 13.2 μM) that was used as inspiration in the design of new quinolin-2(1H)-one analogs [124].

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