The discovery of potent, selective, and orally bioavailable PDE9 inhibitors as potential hypoglycemic agents

DeNinno, Michael P.; Andrews, Melissa P.; Bell, Andrew S.; Chen, Yue; Eller-Zarbo, Cynthia; Eshelby, Nan; Etienne, John B.; Moore, Dianna E.; Palmer, Michael; Visser, Michael; Yu, Lap-Fai; Zavadoski, William J.; Gibbs, E. Michael

doi:10.1016/j.bmcl.2009.03.024

Cited by 42 publications

(89 citation statements)

References 18 publications

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“…The remaining PDE families are capable of degrading both substrates. PDE9 inhibitors have been studied for their potential applications to treat diabetes (Deninno et al, 2009;Shao et al, 2014) and central nervous system diseases such as Alzheimer's disease (Wunder et al, 2005;van der Staay et al, 2008;Verhoest et al, 2009Verhoest et al, , 2012Hutson et al, 2011;Vardigan et al, 2011;Claffey et al, 2012;Kleiman et al, 2012;Kroker et al, 2012Kroker et al, , 2014Liddie et al, 2012;Schwam et al, 2014;Singh and Patra, 2014;Heckman et al, 2015;Nagy et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor

et al. 2015

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Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of central nervous system diseases and diabetes. Here, we report the discovery of a new category of PDE9 inhibitors by rational design on the basis of the crystal structures. The best compound, (S), has an IC 50 value of 11 nM against PDE9 and the racemic C33 has bioavailability of 56.5% in the rat pharmacokinetic model. The crystal structures of PDE9 in the complex with racemic C33, (R)-C33, and (S)-C33 reveal subtle conformational asymmetry of two M-loops in the PDE9 dimer and different conformations of two C33 enantiomers. The structures also identified a small hydrophobic pocket that interacts with the tyrosyl tail of (S)-C33 but not with (R)-C33, and is thus possibly useful for improvement of selectivity of PDE9 inhibitors. The asymmetry of the M-loop and the different interactions of the C33 enantiomers imply the necessity to consider the whole PDE9 dimer in the design of inhibitors.

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Section: Introductionmentioning

confidence: 99%

Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor

et al. 2015

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“…From these analyses potential template proteins were identified and additional criteria were examined to select the most appropriate crystal structure for homology modelling purposes. Compounds De Ninno 1 and De Ninno 14 were taken from the study by De Ninno and coworkers [31] while compound Beghyn 10 was taken from the research recently described by Beghyn et al [22], and in each case utilises their numbering schemes Model building and minimisation Each homology model was generated using Prime version 2.2 (Maestro version 9.1, Schrödinger, LLC, New York, USA) employing the optimised sequence alignment. The model building process used the PDE9A structure 3DYN [29] and retained the endogenous cGMP ligand, metal ions together with their coordinated water molecules.…”

Section: Sequence Alignment Template Selectionmentioning

confidence: 99%

Active site similarity between human and Plasmodium falciparum phosphodiesterases: considerations for antimalarial drug design

Howard

Thompson

Manallack

2011

J Comput Aided Mol Des

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The similarity between Plasmodium falciparum phosphodiesterase enzymes (PfPDEs) and their human counterparts have been examined and human PDE9A was found to be a suitable template for the construction of homology models for each of the four PfPDE isoforms. In contrast, the architecture of the active sites of each model was most similar to human PDE1. Molecular docking was able to model cyclic guanosine monophosphate (cGMP) substrate binding in each case but a docking mode supporting cyclic adenosine monophosphate (cAMP) binding could not be found. Anticipating the potential of PfPDE inhibitors as anti-malarial drugs, a range of reported PDE inhibitors including zaprinast and sildenafil were docked into the model of PfPDEα. The results were consistent with their reported biological activities, and the potential of PDE1/9 inhibitor analogues was also supported by docking.

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“…The CNS MPO includes ionization constant (pKa), log P, and log D 7.4 . This emphasizes the importance of ionization and lipophilicity adjusted for ionization [13,23,28,29]. Recently Z. Ranković further refined the CNS desirability criteria in CNS MPOv.2 [30].…”

Section: Lipophilicity and Oral Absorptionmentioning

confidence: 99%

Leveraging chromatography based physicochemical properties for efficient drug design

Goetz

Shalaeva²

2018

ADMET DMPK

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<p class="ADMETabstracttext">Applications of chromatography derived lipophilicity, polarity, and 3D concepts such as conformational states, exposed polarity and intramolecular hydrogen bonds (IMHB), are discussed along with recently developed methods for incorporating these concepts into drug design strategies. In addition, the drug design process is described with examples and practices used at Pfizer, as well as experimental and computed parameters used for parallel optimization of properties leading to drug candidate nominations.</p>

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The discovery of potent, selective, and orally bioavailable PDE9 inhibitors as potential hypoglycemic agents

Cited by 42 publications

References 18 publications

Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor

Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor

Active site similarity between human and Plasmodium falciparum phosphodiesterases: considerations for antimalarial drug design

Leveraging chromatography based physicochemical properties for efficient drug design

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