Solubility-Driven Optimization of Phosphodiesterase-4 Inhibitors Leading to a Clinical Candidate

Press, Neil J.; Taylor, Roger; Fullerton, Joseph D.; Tranter, Pamela; McCarthy, Clive; Keller, Thomas H.; Arnold, Nicola; Beer, David; Brown, Lyndon; Cheung, Robert; Christie, Julie; Denholm, Alastair A.; Haberthuer, Sandra; Hatto, Julia; Keenan, Mark; Mercer, Mark; Oakman, Helen; Sahri, Helene; Tuffnell, Andrew R.; Tweed, Morris; Tyler, John W.; Wagner, Trixie; Fozard, John R.; Trifilieff, Alexandre

doi:10.1021/jm300459a

Cited by 30 publications

(28 citation statements)

References 15 publications

(17 reference statements)

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“…Compound 4 was then converted into (-)-1 in 3.2% overall yield via a seventeen-step reaction sequence. 19 In 2014, in the context of a study on the synthesis of aporphines and their evaluation as ligands for 5-HT 2A receptors implicated in several neuropsychiatric maladies, 22 Harding and co-workers synthesized compound 6 ( Figure 3), 23 which is an analogue of nantenine (7), an aporphine alkaloid first isolated from Cassytha filiformis. 24…”

Section: Methodsmentioning

confidence: 99%

“…[8-(3-fluorophenyl)-1,7-naphthyridin-6-yl]-trans-cyclohexanecarboxylic acid (C), an improved PDE4 inhibitor for the treatment of chronic obstructive pulmonary disease; 7 the mTOR inhibitor D; 8 the herbicidal compound E; 9 GDC-0941, a PI3K inhibitor; 10 AMG 900, a highly selective, orally bioavailable inhibitor of Aurora kinases with activity against multidrug-resistant cancer cell lines; 11 the potent ROR γ γ inverse agonist F; 12 the potent γ-secretase inhibitor anilinotriazole G; 13 and 9H-carbazole-1-carboxamide H, a potent and selective JAK2 inhibitor. 14 Unfortunately, this scalable, functional-group-tolerant regioselective cross-coupling reaction suffers from lack of step-and atom-economy since the activating groups present in both partners of the catalytic cross-coupling need to be synthesized, frequently by multi-step reaction sequences, and are not present in the required cross-coupling products.…”

Section: Review Syn Thesismentioning

confidence: 99%

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Direct (Hetero)arylation Reactions of (Hetero)arenes as Tools for the Step- and Atom-Economical Synthesis of Biologically Active Unnatural Compounds Including Pharmaceutical Targets

et al. 2016

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The significant number of papers and reviews published in this last decade testifies to the utility of the transition-metal-catalyzed direct C–H (hetero)arylation reactions of (hetero)arenes as efficient and powerful tools for the step- and atom-economical, regio- and chemoselective synthesis of natural and unnatural compounds. However, no review has so far been devoted to summarizing the application of these reactions in the synthesis of biologically active compounds. This review with 341 references aims to fill this gap, providing a comprehensive picture of the transition-metal-catalyzed intra- and intermolecular direct C–H (hetero)arylation reactions of (hetero)arenes with (hetero)aryl halides or pseudohalides that have been used as key steps of syntheses of unnatural biologically relevant compounds including pharmaceutical targets, up to the end of September 2015. Attention has also been directed to provide a brief description of the biological properties of the synthesized compounds. 1 Introduction 2 Syntheses via Intramolecular Direct (Hetero)arylation of (Hetero)arene Derivatives 3 Syntheses via Intermolecular Direct (Hetero)arylation Reactions 3.1 Of Arenes 3.2 Of Five-Membered Heteroarenes with One Heteroatom 3.3 Of Five-Membered Heteroarenes with Two Heteroatoms 3.4 Of Five-Membered Heteroarenes with Three and Four Heteroatoms 3.5 Of Five-Membered Heteroarenes Fused to a Six-Membered Heteroarene 3.6 Of Five-Membered Heteroarene Moieties of Tricyclic Heteroarenes 3.7 Of Six-Membered Heteroarenes 4 Syntheses of Nitrogen-Containing Polycyclic Heteroarene via One-Pot Palladium-Catalyzed Domino Direct Arylation/N-Arylation Reactions 5 Conclusion

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Section: Methodsmentioning

confidence: 99%

Section: Review Syn Thesismentioning

confidence: 99%

Direct (Hetero)arylation Reactions of (Hetero)arenes as Tools for the Step- and Atom-Economical Synthesis of Biologically Active Unnatural Compounds Including Pharmaceutical Targets

et al. 2016

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“…5 The inhibition of PDE5 is involved in the development of drugs for the treatment of erectile dysfunction. 7 Although the effectiveness of PDE4 inhibitors for the treatment of airway inflammation is highly supported 8 , the clinical use of PDE4 inhibitors seems to be restricted by the presence of prominent side effects, like nausea, emesis and sedation. 7 Although the effectiveness of PDE4 inhibitors for the treatment of airway inflammation is highly supported 8 , the clinical use of PDE4 inhibitors seems to be restricted by the presence of prominent side effects, like nausea, emesis and sedation.…”

Section: Introductionmentioning

confidence: 99%

Exhaustive 3D-QSAR analyses as a computational tool to explore the potency and selectivity profiles of thieno[3,2-d]pyrimidin-4(3H)-one derivatives as PDE7 inhibitors

et al. 2016

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Exhaustive 3D-QSAR analyses as a computational tool to explore the potency and selectivity profiles of thieno[3,2-d]pyrimidin-4(3H)-one derivatives as PDE7 inhibitors AbstractThe development of selective ligands binding to specific PDE isoforms represent an urgent need in medicinal chemistry, being a necessary strategy to identify much more drug-like compounds, to be investigated for several therapies. Concerning inflammation, rational design of selective PDE7inhibitors over PDE4 could lead to derivatives endowed with a better safety profile, showing limited side-effects. In this context, thieno[3,2-d]pyrimidin-4(3H)-one-based compounds have been recently studied as a series of potent phosphodiesterase type 7 (PDE7) inhibitors, being most of them selective over other PDE enzymes, such as PDE4B. This work describes a computational study based on docking calculations followed by Comparative Molecular Fields Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA), in order to better elucidate the pharmacophore features of this series of PDE7 inhibitors. The results reveal the ligand-based approach as a promising strategy to better investigate the potency and selectivity issues of PDE7inhibitors. In addition, the results also allowed to obtain robust statistical models able to predict the potency and selectivity trend of new analogues prior to synthesis.Any further detail concerning the (standard) CoMFA and CoMSIA procedures and the statistical and predictive evaluation we applied, were previously reported in a consistent number of our works. [36][37][38][39][40][41] Acknowledgements This work was financially supported by the University of Genoa. Authors would like to thank Mr.V. Ruocco for the informatic support to calculations.Exhaustive 3D-QSAR analyses as a computational tool to explore the potency and selectivity profiles of thieno[3,2-d]pyrimidin-4(3H)-one derivatives as PDE7 inhibitorsExhaustive 3D-QSAR analyses as a computational tool to explore the potency and selectivity profiles of thieno[3,2-d]pyrimidin-4(3H)-one derivatives as PDE7 inhibitors

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“…) , pyrazolopyridines , and the 1,7‐naphthyridines (Fig. ) are of particular interest in this field. Furthermore, N ‐acylhydrazones are also potent PDE inhibitors ; substitution of the N ‐acylhydrazone scaffold to quinazoline scaffold proved to be an effective tool for lead optimization strategy as shown in Fig.…”

Section: Introductionmentioning

confidence: 99%

Novel Quinazolin‐4(3H)‐one/Schiff Base Hybrids as Antiproliferative and Phosphodiesterase 4 Inhibitors: Design, Synthesis, and Docking Studies

Abdel‐Rahman

Abdel‐Aziz

Canzoneri

et al. 2014

Archiv der Pharmazie

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A novel series of quinazolin-4(3H)-one/Schiff base hybrids was rationally designed and synthesized. The prepared compounds were evaluated for in vitro activity to inhibit phosphodiesterase 4 (PDE4), where several of them showed good-to-moderate activity compared to rolipram. Compound 7 showed potent PDE4 inhibition in this series, with an IC50 of 1.60 µM. Compounds that showed PDE4 inhibition were further assessed for antiproliferative activity using different human tumor cell lines. Compound 10 exhibited significant antiproliferative activity with IC50 values of 140, 79, and 320 nM in breast, lung, and colon tumor cells, respectively. Docking of compound 7 in the active site of PDE4B illustrates its possible binding mode and provides insight for further optimizations of this novel scaffold for inhibiting PDE4.

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Solubility-Driven Optimization of Phosphodiesterase-4 Inhibitors Leading to a Clinical Candidate

Cited by 30 publications

References 15 publications

Direct (Hetero)arylation Reactions of (Hetero)arenes as Tools for the Step- and Atom-Economical Synthesis of Biologically Active Unnatural Compounds Including Pharmaceutical Targets

Direct (Hetero)arylation Reactions of (Hetero)arenes as Tools for the Step- and Atom-Economical Synthesis of Biologically Active Unnatural Compounds Including Pharmaceutical Targets

Exhaustive 3D-QSAR analyses as a computational tool to explore the potency and selectivity profiles of thieno[3,2-d]pyrimidin-4(3H)-one derivatives as PDE7 inhibitors

Novel Quinazolin‐4(3H)‐one/Schiff Base Hybrids as Antiproliferative and Phosphodiesterase 4 Inhibitors: Design, Synthesis, and Docking Studies

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