Discovery of diarylurea P2Y1 antagonists with improved aqueous solubility

Wang, Tammy C.; Qiao, Jennifer X.; Clark, C. G.; Jua, Ji; Price, Laura A.; Wu, Qimin; Chang, Ming; Zheng, Joanna J.; Huang, Christine; Everlof, Gerry; Schumacher, William A.; Wong, Pancras C.; Seiffert, Dietmar; Stewart, Anne B.; Bostwick, Jeffrey S.; Crain, Earl J.; Watson, Carol A.; Rehfuss, Robert; Wexler, Ruth R.; Lam, Patrick Y.S.

doi:10.1016/j.bmcl.2013.03.125

Cited by 17 publications

(15 citation statements)

References 30 publications

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“…Unlike the nucleotide‐like ligand MRS2500 whose binding site is within the receptor helical bundle, the non‐nucleotide antagonist BPTU binds to the receptor in a shallow binding pocket on the external interface of TM1–TM3 with the lipid bilayer, which accommodates the ligand mainly through hydrophobic interactions. This hydrophobic binding environment of BPTU is consistent with the high hydrophobicity of this ligand, and previous efforts showing that addition of any polar groups to reduce its lipophilicity decreased binding affinity to P2Y 1 receptors (Wang, Qiao, et al, 2013). The unique binding site of BPTU indicates that this ligand acts as an allosteric modulator of P2Y 1 receptors .…”

Section: Structural Characterization Of P2y Receptorssupporting

confidence: 86%

“…The non‐nucleotide compound MRS2950 ( 11 ) was identified by virtual screening of the modelled receptor orthosteric site (Costanzi, Kumar, Balasubramanian, Harden, & Jacobson, 2012). Another non‐nucleotide compound, BPTU ( N ‐[2‐[2‐(1,1‐dimethylethyl)phenoxy]‐3‐pyridinyl]‐ N ′‐[4‐(trifluoromethoxy)phenyl]urea, 12 ) and its analogues act as an allosteric inhibitors (Gao & Jacobson, 2017; Peng et al, 2018; Wang, Qiao, et al, 2013; Yuan et al, 2016; Zhang, Gao, et al, 2015).…”

Section: Selective Ligand Tools To Study P2y Receptorsmentioning

confidence: 99%

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Update of P2Y receptor pharmacology: IUPHAR Review 27

Jacobson

Delicado

Gachet

et al. 2020

British J Pharmacology

170

184

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Eight G protein-coupled P2Y receptor subtypes respond to extracellular adenine and uracil mononucleotides and dinucleotides. P2Y receptors belong to the δ group of rhodopsin-like GPCRs and contain two structurally distinct subfamilies: P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 (principally G q protein-coupled P2Y 1 -like) and P2Y 12-14 (principally G i protein-coupled P2Y 12 -like) receptors. Brain P2Y receptors occur in neurons, glial cells, and vasculature. Endothelial P2Y 1 , P2Y 2 , P2Y 4 , and P2Y 6 receptors induce vasodilation, while smooth muscle P2Y 2 , P2Y 4 , and P2Y 6 receptor activation leads to vasoconstriction. Pancreatic P2Y 1 and P2Y 6 receptors stimulate while P2Y 13 receptors inhibits insulin secretion. Antagonists of P2Y 12 receptors, and potentially P2Y 1 receptors, are anti-thrombotic agents, and a P2Y 2 /P2Y 4 receptor agonist treats dry eye syndrome in Asia. P2Y receptor agonists are generally pro-inflammatory, and antagonists may eventually treat inflammatory conditions. This article reviews recent developments in P2Y receptor pharmacology (using synthetic agonists and antagonists), structure and biophysical properties (using X-ray crystallography, mutagenesis and modelling), physiological and pathophysiological roles, and present and potentially future therapeutic targeting.Abbreviations: BMD, bone mineral density; DUSP, dual specificity protein phosphatase; ECL, extracellular loop; EPAC, exchange protein activated by cAMP; KO, knockout; MSD, musculoskeletal disorder; SNP, single nucleotide polymorphism; SS, Sjögren's syndrome; TM, transmembrane helix.

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Section: Structural Characterization Of P2y Receptorssupporting

confidence: 86%

Section: Selective Ligand Tools To Study P2y Receptorsmentioning

confidence: 99%

Update of P2Y receptor pharmacology: IUPHAR Review 27

Jacobson

Delicado

Gachet

et al. 2020

British J Pharmacology

170

184

View full text Add to dashboard Cite

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“…Previous efforts to reduce the lipophilicity of BPTU (HPLC log P = 5.7) have shown that adding polar or basic amine groups to this ligand decreases binding affinity and antiplatelet activity; in fact, the binding affinity in this chemical series correlates directly with the HPLC log P value 24 . These data agree with our structure where the ligand BPTU binds in a highly hydrophobic environment.…”

Section: A Unique Binding Site For Bptumentioning

confidence: 99%

“…This carbonyl is available for bidentate coordination of this selective P2Y 1 R antagonist because the residue P105 2.58 above precludes intrahelical hydrogen-bonding. Previous structure-activity relationship (SAR) studies demonstrated that replacing the urea linker of BPTU with other two to four atom linkers greatly reduced potency 24 . This could be explained by the importance of the two hydrogen-bond interactions for retaining P2Y 1 R binding affinity of this chemical series.…”

Section: A Unique Binding Site For Bptumentioning

confidence: 99%

Two disparate ligand-binding sites in the human P2Y1 receptor

Zhang

Gao

Zhang

et al. 2015

Nature

317

323

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In response to adenosine 5′-diphosphate, the P2Y1 receptor (P2Y1R) facilitates platelet aggregation, and thus serves as an important antithrombotic drug target. Here we report the crystal structures of the human P2Y1R in complex with a nucleotide antagonist MRS2500 at 2.7Å resolution, and with a non-nucleotide antagonist BPTU at 2.2Å resolution. The structures reveal two distinct ligand binding sites, providing atomic details of P2Y1R’s unique ligand binding modes. MRS2500 recognizes a binding site within the seven transmembrane bundle of P2Y1R, which, however, is different in shape and location from the nucleotide binding site in previously determined P2Y12R structure. BPTU binds to an allosteric pocket on the external receptor interface with the lipid bilayer, making it the first structurally characterized selective G protein-coupled receptor (GPCR) ligand located entirely outside of the helical bundle. These high-resolution insights into P2Y1R should enable discovery of new orthosteric and allosteric antithrombotic drugs with reduced adverse effects.

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“…BMS scientists addressed this issue by adding an amine-containing water-solubilizing group (R 3 ) onto the distal phenyl ring (Figure ). This afforded a series of compounds, as illustrated by 14 and 15 , with comparable binding affinities compared to the parent 13 . Compound 14 was chosen as the new lead compound because it possessed similar levels of activity in the platelet aggregation assay (IC 50 = 2.9 μM at 25 μM ADP) but had significantly higher solubility.…”

Section: Drug-like Antagonists Of the P2y1 Receptor (P2y1r)mentioning

confidence: 99%

Drug-like Antagonists of P2Y Receptors—From Lead Identification to Drug Development

et al. 2016

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P2Y receptors are expressed in virtually all cells and tissue types and mediate an astonishing array of biological functions including platelet aggregation, smooth muscle cell proliferation and immune regulation. The P2Y receptors belong to the GPCR superfamily and are composed of eight members encoded by distinct genes that can be subdivided into two groups based on their coupling to specific G-proteins. Extensive research has been undertaken to find modulators of P2Y receptors, although to date there have only been a limited number of small molecule P2Y receptor antagonists that have been approved by drug/medicines agencies. This Perspective reviews the known P2Y receptor antagonists, highlighting oral drug-like receptor antagonists, and considers future opportunities for the development of small molecules for clinical evaluation.

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Discovery of diarylurea P2Y1 antagonists with improved aqueous solubility

Cited by 17 publications

References 30 publications

Update of P2Y receptor pharmacology: IUPHAR Review 27

Update of P2Y receptor pharmacology: IUPHAR Review 27

Two disparate ligand-binding sites in the human P2Y1 receptor

Drug-like Antagonists of P2Y Receptors—From Lead Identification to Drug Development

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