DENUFOSOL


Synonyms	Denufosol
Status
Molecule Category	UNKNOWN
UNII	5PC250KSSH


Active Pharmaceutical Ingredients Bioactive chemicals	Exact Similarity SubStructure	Threshold (%) >= 70

Structure


InChI Key	FPNPSEMJLALQSA-MIYUEGBISA-N
Smiles	Nc1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4ccc(=O)[nH]c4=O)[C@H](O)[C@@H]3O)O2)c(=O)n1
InChI	InChI=1S/C18H27N5O21P4/c19-11-1-3-22(17(28)20-11)13-5-8(24)9(40-13)6-38-45(30,31)42-47(34,35)44-48(36,37)43-46(32,33)39-7-10-14(26)15(27)16(41-10)23-4-2-12(25)21-18(23)29/h1-4,8-10,13-16,24,26-27H,5-7H2,(H,30,31)(H,32,33)(H,34,35)(H,36,37)(H2,19,20,28)(H,21,25,29)/t8-,9+,10+,13+,14+,15+,16+/m0/s1

Physicochemical Descriptors

Property Name	Value
Molecular Formula	C18H27N5O21P4
Molecular Weight	773.32
AlogP	-2.87
Hydrogen Bond Acceptor	21.0
Hydrogen Bond Donor	9.0
Number of Rotational Bond	14.0
Polar Surface Area	390.27
Molecular species	ACID
Aromatic Rings	2.0
Heavy Atoms	48.0

Reference

Journal : J. Med. Chem.

Title : Molecular modeling of the human P2Y2 receptor and design of a selective agonist, 2'-amino-2'-deoxy-2-thiouridine 5'-triphosphate.

PubMed ID : 17302398

DOI : 10.1021/jm060903o

Year : 2007

Volume : 50

Issue : 6

First Page : 1166

Last Page : 1176

Authors : Ivanov AA, Ko H, Cosyn L, Maddileti S, Besada P, Fricks I, Costanzi S, Harden TK, Calenbergh SV, Jacobson KA.

Abstract : A rhodopsin-based homology model of the nucleotide-activated human P2Y2 receptor, including loops, termini, and phospholipids, was optimized with the Monte Carlo multiple minimum conformational search routine. Docked uridine 5'-triphosphate (UTP) formed a nucleobase pi-pi complex with conserved Phe3.32. Selectivity-enhancing 2'-amino-2'-deoxy substitution interacted through pi-hydrogen-bonding with aromatic Phe6.51 and Tyr3.33. A "sequential ligand composition" approach for docking the flexible dinucleotide agonist Up4U demonstrated a shift of conserved cationic Arg3.29 from the UTP gamma position to the delta position of Up4U and Up4 ribose. Synthesized nucleotides were tested as agonists at human P2Y receptors expressed in 1321N1 astrocytoma cells. 2'-Amino and 2-thio modifications were synergized to enhance potency and selectivity; compound 8 (EC50 = 8 nM) was 300-fold P2Y2-selective versus P2Y4. 2'-Amine acetylation reduced potency, and trifluoroacetylation produced intermediate potency. 5-Amino nucleobase substitution did not enhance P2Y2 potency through a predicted hydrophilic interaction possibly because of destabilization of the receptor-favored Northern conformation of ribose. This detailed view of P2Y2 receptor recognition suggests mutations for model validation.

Reference

Journal : Bioorg. Med. Chem.

Title : Synthesis and potency of novel uracil nucleotides and derivatives as P2Y2 and P2Y6 receptor agonists.

PubMed ID : 18514530

DOI : 10.1016/j.bmc.2008.05.013

Year : 2008

Volume : 16

Issue : 12

First Page : 6319

Last Page : 6332

Authors : Ko H, Carter RL, Cosyn L, Petrelli R, de Castro S, Besada P, Zhou Y, Cappellacci L, Franchetti P, Grifantini M, Van Calenbergh S, Harden TK, Jacobson KA.

Abstract : The phosphate, uracil, and ribose moieties of uracil nucleotides were varied structurally for evaluation of agonist activity at the human P2Y(2), P2Y(4), and P2Y(6) receptors. The 2-thio modification, found previously to enhance P2Y(2) receptor potency, could be combined with other favorable modifications to produce novel molecules that exhibit high potencies and receptor selectivities. Phosphonomethylene bridges introduced for stability in analogues of UDP, UTP, and uracil dinucleotides markedly reduced potency. Truncation of dinucleotide agonists of the P2Y(2) receptor, in the form of Up(4)-sugars, indicated that a terminal uracil ring is not essential for moderate potency at this receptor and that specific SAR patterns are observed at this distal end of the molecule. Key compounds reported in this study include 9, alpha,beta-methylene-UDP, a P2Y(6) receptor agonist; 30, Up(4)-phenyl ester and 34, Up(4)-[1]glucose, selective P2Y(2) receptor agonists; dihalomethylene phosphonate analogues 16 and 41, selective P2Y(2) receptor agonists; 43, the 2-thio analogue of INS37217 (P(1)-(uridine-5')-P(4)-(2'-deoxycytidine-5')tetraphosphate), a potent and selective P2Y(2) receptor agonist.

Reference

Journal : Bioorg. Med. Chem.

Title : Synthesis and potency of novel uracil nucleotides and derivatives as P2Y2 and P2Y6 receptor agonists.

PubMed ID : 18514530

DOI : 10.1016/j.bmc.2008.05.013

Year : 2008

Volume : 16

Issue : 12

First Page : 6319

Last Page : 6332

Authors : Ko H, Carter RL, Cosyn L, Petrelli R, de Castro S, Besada P, Zhou Y, Cappellacci L, Franchetti P, Grifantini M, Van Calenbergh S, Harden TK, Jacobson KA.

Reference

Journal : Bioorg. Med. Chem.

Title : Synthesis and potency of novel uracil nucleotides and derivatives as P2Y2 and P2Y6 receptor agonists.

PubMed ID : 18514530

DOI : 10.1016/j.bmc.2008.05.013

Year : 2008

Volume : 16

Issue : 12

First Page : 6319

Last Page : 6332

Authors : Ko H, Carter RL, Cosyn L, Petrelli R, de Castro S, Besada P, Zhou Y, Cappellacci L, Franchetti P, Grifantini M, Van Calenbergh S, Harden TK, Jacobson KA.

Reference

Journal : J. Med. Chem.

Title : 5-OMe-UDP is a potent and selective P2Y(6)-receptor agonist.

PubMed ID : 20095577

DOI : 10.1021/jm901450d

Year : 2010

Volume : 53

Issue : 4

First Page : 1673

Last Page : 1685

Authors : Ginsburg-Shmuel T, Haas M, Schumann M, Reiser G, Kalid O, Stern N, Fischer B.

Abstract : P2Y nucleotide receptors (P2Y-Rs) play important physiological roles. However, most of the P2Y-R subtypes are still lacking potent and selective agonists and antagonists. Based on data mining analysis of binding interactions in 44 protein-uridine nucleos(t)ides complexes, we designed uracil nucleotides, substituted at the C5/C6 position. All C6-substituted derivatives were inactive at the P2Y(2,4,6)-Rs, while out of the C5-substituted analogues, only 5-OMe-UD(T)P showed activity. To rationalize the data, the ionization and conformation of these analogues were evaluated. The pK(a) values of most analogues substituted at the C5/C6 positions were unaltered compared to UTP (pK(a) 9.42), except for 5-F-UTP nucleotide (pK(a) 7.85). C6-substituted analogues adopt the syn or high-syn conformations, which are disfavored by the receptors, while 5-OMe-UD(T)P adopt the favored anti conformation. Furthermore, 5-OMe-UDP adopts the S sugar puckering, which is the conformation preferred by the P2Y(6)-R, but not the P2Y(2)- or P2Y(4)-Rs. 5-OMe-UDP fulfills the conformational and H-bonding requirements of P2Y(6)-R, thus, making a potent P2Y(6)-R agonist (EC(50) 0.08 microM), more than UDP (EC(50) 0.14 microM).

Assay Description	Organism	Bioactivity
Agonist activity at human recombinant P2Y2 receptor expressed in 1321N1 cells assessed as stimulation of phospholipase C	Homo sapiens	270.0 nM
Agonist activity at human P2Y6 receptor expressed in human 1321N1 cells assessed as [3H]inositol phosphate accumulation by scintillation proximity assay	Homo sapiens	950.0 nM
Agonist activity at human P2Y2 receptor expressed in human 1321N1 cells assessed as [3H]inositol phosphate accumulation by scintillation proximity assay	Homo sapiens	140.0 nM
Agonist activity at human P2Y4 receptor expressed in human 1321N1 cells assessed as [3H]inositol phosphate accumulation by scintillation proximity assay	Homo sapiens	140.0 nM
Agonist activity at human P2Y2 receptor expressed in human 1321N1 cells assessed as calcium elevation by fura2/AM assay	Homo sapiens	220.0 nM

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Cross References

Resources	Reference
ChEMBL	CHEMBL507282
DrugBank	DB04983
FDA SRS	5PC250KSSH
Guide to Pharmacology	1737
PubChem	9875516
ZINC	ZINC000085540154

CONTENTS

Structure
Chemical and Physical Properties
Related Entries