Repurposing Human <scp>PDE</scp>4 Inhibitors for Neglected Tropical Diseases. Evaluation of Analogs of the Human <scp>PDE</scp>4 Inhibitor <scp>GSK</scp>‐256066 as Inhibitors of <scp>PDEB</scp>1 of <i>Trypanosoma brucei</i>

Human African trypanosomiasis (HAT) is a deadly disease in need of new chemotherapeutics that can cross into the central nervous system. We previously reported the discovery of 2 (NEU-617), a small molecule with activity against T. brucei bloodstream proliferation. Further optimization of 2 to improve the physicochemical properties (LogP, LLE,[1] and MPO score)[2] have led us to twelve sub-micromolar compounds, most importantly the headgroup variants 9i and 9j, and the linker variant 18. Although these 3 compounds had reduced potency compared to 2, they all had improved LogP, LLE and MPO scores. Cross-screening these analogs against other protozoan parasites uncovered 9o with potent activity towards T. brucei, T. cruzi and L. major, while four others compounds (17, 18, 21, 26) showed activity towards P. falciparum D6. This reinforces the effectiveness of lead repurposing for the discovery of new protozoan disease therapeutics.

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“…Our previous lead repurposing work has primarily focused on inhibitors of phosphodiesterases[5–10] and protein kinases [11–16]. …”

Section: Introductionmentioning

confidence: 99%

Optimization of physicochemical properties for 4-anilinoquinazoline inhibitors of trypanosome proliferation

Woodring

Bachovchin

Brady

et al. 2017

European Journal of Medicinal Chemistry

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“…Conjugating the quinolinone-containing orthostere GS-709344 (referred to as b2A), which confers b 2 -adrenoceptor agonism in several LABAs, including indacaterol, carmoterol, and abediterol (Montuschi and Ciabattoni, 2015), to a close structural analog of GSK 256066 [GSK 256066a; compound 12b in Ochiana et al (2015)] by a pent-1-yn-1ylbenzene spacer afforded the bifunctional compound GS-5759 ( Fig. 1; Baker et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

“…The dual pharmacology of GS-5759 is attributable to two structural elements linked covalently by a pent-1-yn-1ylbenzene spacer: 1) a quinolinone-based orthostere, which is a well recognized pharmacophore conferring b 2 -adrenoceptor agonism (Yoshizaki et al, 1976;Milecki et al, 1987) and is found in batefenterol (Hughes et al, 2015) and related MABAs, including biphenyl-2-yl-carbamic acid 1-{9-[(R)-2hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)-ethylamino]-nonyl}-piperidin-4-yl ester (THRX 198321) and biphenyl-2-ylcarbamic acid 1-{3-[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenoxy)phenyl]propyl piperidin-4-yl ester (THRX 200495) (McNamara et al, 2012); and 2) a quinoline 3-carboxamide present in GSK 256066a (Ochiana et al, 2015), which has low picomolar affinity for PDE4 (Table 1).…”

Section: Discussionmentioning

confidence: 99%

GS-5759, a Bifunctionalβ₂-Adrenoceptor Agonist and Phosphodiesterase 4 Inhibitor for Chronic Obstructive Pulmonary Disease with a Unique Mode of Action: Effects on Gene Expression in Human Airway Epithelial Cells

Joshi

Dong

Hamed

et al. 2016

J Pharmacol Exp Ther

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(R)-6-[(3-{[4-(5-{[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}pent-1-yn-1-yl)phenyl] carbamoyl}phenyl)sulphonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide trifluoroacetic acid (GS-5759) is a bifunctional ligand composed of a quinolinone-containing pharmacophore [β-adrenoceptor agonist orthostere (β2A)] found in several β-adrenoceptor agonists, including indacaterol, linked covalently to a phosphodiesterase 4 (PDE4) inhibitor related to 6-[3-(dimethylcarbamoyl)benzenesulphonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GSK 256066) by a pent-1-yn-1-ylbenzene spacer. GS-5759 had a similar affinity for PDE4B1 and the native β-adrenoceptor expressed on BEAS-2B human airway epithelial cells. However, compared with the monofunctional parent compound, β2A, the K of GS-5759 for the β-adrenoceptor was 35-fold lower. Schild analysis determined that the affinities of the β-adrenoceptor antagonists, (2R,3R)-1-[(2,3-dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl) amino]-2-butanol (ICI 118551) and propranolol, were agonist-dependent, being significantly lower for GS-5759 than β2A. Collectively, these data can be explained by "forced proximity," bivalent binding where the pharmacophore in GS-5759 responsible for PDE4 inhibition also interacts with a nonallosteric domain within the β-adrenoceptor that enhances the affinity of β2A for the orthosteric site. Microarray analyses revealed that, after 2-hour exposure, GS-5759 increased the expression of >3500 genes in BEAS-2B cells that were highly rank-order correlated with gene expression changes produced by indacaterol and GSK 256066 in combination (Ind/GSK). Moreover, the line of regression began close to the origin with a slope of 0.88, indicating that the magnitude of most gene expression changes produced by Ind/GSK was quantitatively replicated by GS-5759. Thus, GS-5759 is a novel compound exhibiting dual β-adrenoceptor agonism and PDE4 inhibition with potential to interact on target tissues in a synergistic manner. Such polypharmacological behavior may be particularly effective in chronic obstructive pulmonary disease and other complex disorders where multiple processes interact to promote disease pathogenesis and progression.

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“…Interestingly, the H-loop contains a residue, Asp-1151, which is unique in GlPDE in terms of its physico-chemical properties since all hPDEs contain a polar but uncharged amino acid (Asn,Thr or Ser) at this position ( S3 Fig ). In various human and kinetoplastid PDEs the corresponding residue forms a part of the catalytic pocket and has been recognized as an anchor point for inhibitors to increase isozyme selectivity [ 58 – 63 ].…”

Section: Resultsmentioning

confidence: 99%

The single cyclic nucleotide-specific phosphodiesterase of the intestinal parasite Giardia lamblia represents a potential drug target

et al. 2017

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BackgroundGiardiasis is an intestinal infection correlated with poverty and poor drinking water quality, and treatment options are limited. According to the Center for Disease Control and Prevention, Giardia infections afflict nearly 33% of people in developing countries, and 2% of the adult population in the developed world. This study describes the single cyclic nucleotide-specific phosphodiesterase (PDE) of G. lamblia and assesses PDE inhibitors as a new generation of anti-giardial drugs.MethodsAn extensive search of the Giardia genome database identified a single gene coding for a class I PDE, GlPDE. The predicted protein sequence was analyzed in-silico to characterize its domain structure and catalytic domain. Enzymatic activity of GlPDE was established by complementation of a PDE-deficient Saccharomyces cerevisiae strain, and enzyme kinetics were characterized in soluble yeast lysates. The potency of known PDE inhibitors was tested against the activity of recombinant GlPDE expressed in yeast and against proliferating Giardia trophozoites. Finally, the localization of epitope-tagged and ectopically expressed GlPDE in Giardia cells was investigated.ResultsGiardia encodes a class I PDE. Catalytically important residues are fully conserved between GlPDE and human PDEs, but sequence differences between their catalytic domains suggest that designing Giardia-specific inhibitors is feasible. Recombinant GlPDE hydrolyzes cAMP with a Km of 408 μM, and cGMP is not accepted as a substrate. A number of drugs exhibit a high degree of correlation between their potency against the recombinant enzyme and their inhibition of trophozoite proliferation in culture. Epitope-tagged GlPDE localizes as dots in a pattern reminiscent of mitosomes and to the perinuclear region in Giardia.ConclusionsOur data strongly suggest that inhibition of G. lamblia PDE activity leads to a profound inhibition of parasite proliferation and that GlPDE is a promising target for developing novel anti-giardial drugs.

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Repurposing Human PDE4 Inhibitors for Neglected Tropical Diseases. Evaluation of Analogs of the Human PDE4 Inhibitor GSK‐256066 as Inhibitors of PDEB1 of Trypanosoma brucei

Cited by 14 publications

References 27 publications

Optimization of physicochemical properties for 4-anilinoquinazoline inhibitors of trypanosome proliferation

Optimization of physicochemical properties for 4-anilinoquinazoline inhibitors of trypanosome proliferation

GS-5759, a Bifunctionalβ₂-Adrenoceptor Agonist and Phosphodiesterase 4 Inhibitor for Chronic Obstructive Pulmonary Disease with a Unique Mode of Action: Effects on Gene Expression in Human Airway Epithelial Cells

The single cyclic nucleotide-specific phosphodiesterase of the intestinal parasite Giardia lamblia represents a potential drug target

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Repurposing Human PDE4 Inhibitors for Neglected Tropical Diseases. Evaluation of Analogs of the Human PDE4 Inhibitor GSK‐256066 as Inhibitors of PDEB1 of Trypanosoma brucei

Cited by 14 publications

References 27 publications

Optimization of physicochemical properties for 4-anilinoquinazoline inhibitors of trypanosome proliferation

Optimization of physicochemical properties for 4-anilinoquinazoline inhibitors of trypanosome proliferation

GS-5759, a Bifunctionalβ2-Adrenoceptor Agonist and Phosphodiesterase 4 Inhibitor for Chronic Obstructive Pulmonary Disease with a Unique Mode of Action: Effects on Gene Expression in Human Airway Epithelial Cells

The single cyclic nucleotide-specific phosphodiesterase of the intestinal parasite Giardia lamblia represents a potential drug target

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GS-5759, a Bifunctionalβ₂-Adrenoceptor Agonist and Phosphodiesterase 4 Inhibitor for Chronic Obstructive Pulmonary Disease with a Unique Mode of Action: Effects on Gene Expression in Human Airway Epithelial Cells