Design, Synthesis, and Biological Evaluation of 3-[4-(2-Hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-<i>b</i>]pyrazin-2(1<i>H</i>)-one, a Potent, Orally Active, Brain Penetrant Inhibitor of Phosphodiesterase 5 (PDE5)

Hughes, Robert; Rogier, D. Joseph; Jacobsen, E. J.; Walker, John K.; MacInnes, Alan; Bond, Brian R.; Zhang, Lena L; Yu, Ying; Zheng, Yi; Rumsey, Jeanne M.; Walgren, Jennie; Curtiss, Sandra W.; Fobian, Yvette M.; Heasley, Steven E.; Cubbage, Jerry W.; Moon, Joseph B.; Brown, David; Acker, Brad A.; Maddux, Todd M.; Tollefson, Mike B.; Mischke, Brent V.; Owen, Dafydd R.; Freskos, John N.; Molyneaux, John M.; Benson, Alan G.; Blevis-Bal, Rhadika M.

doi:10.1021/jm901781q

Cited by 15 publications

(14 citation statements)

References 7 publications

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“…Some drugs utilize a scaffold similar to that of sildenafil and vardenafil, whereas others (e.g., avanafil) have been developed based on novel scaffolds. Pfizer has recently reported novel compounds that are potent and selective PDE5 inhibitors (166,283,381). A collection of analogs of tadalafil have also been developed and tested for blocking tumor growth (1).…”

Section: Pde5 Inhibitorsmentioning

confidence: 99%

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

Francis

Blount

Corbin

2011

Physiological Reviews

567

546

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The superfamily of cyclic nucleotide (cN) phosphodiesterases (PDEs) is comprised of 11 families of enzymes. PDEs break down cAMP and/or cGMP and are major determinants of cellular cN levels and, consequently, the actions of cN-signaling pathways. PDEs exhibit a range of catalytic efficiencies for breakdown of cAMP and/or cGMP and are regulated by myriad processes including phosphorylation, cN binding to allosteric GAF domains, changes in expression levels, interaction with regulatory or anchoring proteins, and reversible translocation among subcellular compartments. Selective PDE inhibitors are currently in clinical use for treatment of erectile dysfunction, pulmonary hypertension, intermittent claudication, and chronic pulmonary obstructive disease; many new inhibitors are being developed for treatment of these and other maladies. Recently reported x-ray crystallographic structures have defined features that provide for specificity for cAMP or cGMP in PDE catalytic sites or their GAF domains, as well as mechanisms involved in catalysis, oligomerization, autoinhibition, and interactions with inhibitors. In addition, major advances have been made in understanding the physiological impact and the biochemical basis for selective localization and/or recruitment of specific PDE isoenzymes to particular subcellular compartments. The many recent advances in understanding PDE structures, functions, and physiological actions are discussed in this review.

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Section: Pde5 Inhibitorsmentioning

confidence: 99%

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

Francis

Blount

Corbin

2011

Physiological Reviews

567

546

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“…This protocol was adapted from Hughes et al . 6-(Trifluoromethyl)pyridin-3-amine (4.00 g, 24.7 mmol) and di- tert -butyl-dicarbonate (6.73 g, 30.9 mmol) were refluxed in 50 mL of anhydrous dioxane.…”

Section: Experimental Sectionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of 4-Quinoline Carboxylic Acids as Inhibitors of Dihydroorotate Dehydrogenase

Madak¹,

Cuthbertson²,

Miyata³

et al. 2018

J. Med. Chem.

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We pursued a structure-guided approach toward the development of improved dihydroorotate dehydrogenase (DHODH) inhibitors with the goal of forming new interactions between DHODH and the brequinar class of inhibitors. Two potential residues, T63 and Y356, suitable for novel H-bonding interactions, were identified in the brequinar-binding pocket. Analogues were designed to maintain the essential pharmacophore and form new electrostatic interactions through strategically positioned H-bond accepting groups. This effort led to the discovery of potent quinoline-based analogues 41 (DHODH IC = 9.71 ± 1.4 nM) and 43 (DHODH IC = 26.2 ± 1.8 nM). A cocrystal structure between 43 and DHODH depicts a novel water mediated H-bond interaction with T63. Additional optimization led to the 1,7-naphthyridine 46 (DHODH IC = 28.3 ± 3.3 nM) that forms a novel H-bond with Y356. Importantly, compound 41 possesses significant oral bioavailability ( F = 56%) and an elimination t = 2.78 h (PO dosing). In conclusion, the data supports further preclinical studies of our lead compounds toward selection of a candidate for early-stage clinical development.

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“…Mesenteric arteriopathy occurred in rats dosed with a concentration of sGCa that lowered blood pressure (Hughes et al 2010). While blood pressure and heart rate were not assessed in the studies described in this report, a cardiovascular functional study was conducted in normal telemetered SD rats using HD-sGCa-A.…”

Section: Discussionmentioning

confidence: 99%

“…The dose selected was based on the maximum tolerated dose identified in an exploratory toxicity study with this compound. This exposure approximated a 10-fold multiple over predicted human efficacious area under the concentration curve (AUC) defined by efficacious blood pressure lowering (10–20 mm Hg in mean arterial pressure) in the spontaneously hypertensive rat (SHR) model (Hughes et al 2010; Webb et al 1998). Five HD-sGCa-A-dosed rats each were sacrificed 24 hr after dosing for 1, 2, 5, and 7 days.…”

Section: Methodsmentioning

confidence: 99%

Oral Administration of Soluble Guanylate Cyclase Agonists to Rats Results in Osteoclastic Bone Resorption and Remodeling with New Bone Formation in the Appendicular and Axial Skeleton

et al. 2014

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Orally administered small molecule agonists of soluble guanylate cyclase (sGC) induced increased numbers of osteoclasts, multifocal bone resorption, increased porosity, and new bone formation in the appendicular and axial skeleton of Sprague-Dawley rats. Similar histopathological bone changes were observed in both young (7-to 9-week-old) and aged (42-to 46-week-old) rats when dosed by oral gavage with 3 different heme-dependent sGC agonist (sGCa) compounds or 1 structurally distinct heme-independent sGCa compound. In a 7-day time course study in 7-to 9-week-old rats, bone changes were observed as early as 2 to 3 days following once daily compound administration. Bone changes were mostly reversed following a 14-day recovery period, with complete reversal after 35 days. The mechanism responsible for the bone changes was investigated in the thyroparathyroidectomized rat model that creates a low state of bone modeling and remodeling due to deprivation of thyroid hormone, calcitonin (CT), and parathyroid hormone (PTH). The sGCa compounds tested increased both bone resorption and formation, thereby increasing bone remodeling independent of calciotropic hormones PTH and CT. Based on these studies, we conclude that the bone changes in rats were likely caused by increased sGC activity.

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Design, Synthesis, and Biological Evaluation of 3-[4-(2-Hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a Potent, Orally Active, Brain Penetrant Inhibitor of Phosphodiesterase 5 (PDE5)

Cited by 15 publications

References 7 publications

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

Design, Synthesis, and Biological Evaluation of 4-Quinoline Carboxylic Acids as Inhibitors of Dihydroorotate Dehydrogenase

Oral Administration of Soluble Guanylate Cyclase Agonists to Rats Results in Osteoclastic Bone Resorption and Remodeling with New Bone Formation in the Appendicular and Axial Skeleton

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