GW813893


Synonyms	Gw813893
Status
Molecule Category	UNKNOWN
UNII	1Y3JD5PEMS


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

Structure


InChI Key	ACEFOQMQINFMRW-DYCFVMESSA-N
Smiles	C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](NS(=O)(=O)/C=C/c2ccc(Cl)s2)C1=O
InChI	InChI=1S/C17H22ClN3O5S2/c1-12(16(22)20-7-9-26-10-8-20)21-6-4-14(17(21)23)19-28(24,25)11-5-13-2-3-15(18)27-13/h2-3,5,11-12,14,19H,4,6-10H2,1H3/b11-5+/t12-,14-/m0/s1

Physicochemical Descriptors

Property Name	Value
Molecular Formula	C17H22ClN3O5S2
Molecular Weight	447.97
AlogP	1.14
Hydrogen Bond Acceptor	6.0
Hydrogen Bond Donor	1.0
Number of Rotational Bond	6.0
Polar Surface Area	96.02
Molecular species	NEUTRAL
Aromatic Rings	1.0
Heavy Atoms	28.0

Reference

Journal : J. Med. Chem.

Title : Factor Xa inhibitors: S1 binding interactions of a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides.

PubMed ID : 17338508

DOI : 10.1021/jm060870c

Year : 2007

Volume : 50

Issue : 7

First Page : 1546

Last Page : 1557

Authors : Chan C, Borthwick AD, Brown D, Burns-Kurtis CL, Campbell M, Chaudry L, Chung CW, Convery MA, Hamblin JN, Johnstone L, Kelly HA, Kleanthous S, Patikis A, Patel C, Pateman AJ, Senger S, Shah GP, Toomey JR, Watson NS, Weston HE, Whitworth C, Young RJ, Zhou P.

Abstract : Factor Xa inhibitory activities for a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides with different P1 groups are described. These data provide insight into binding interactions within the S1 primary specificity pocket; rationales are presented for the derived SAR on the basis of electronic interactions through crystal structures of fXa-ligand complexes and molecular modeling studies. A good correlation between in vitro anticoagulant activities with lipophilicity and the extent of human serum albumin binding is observed within this series of potent fXa inhibitors. Pharmacokinetic profiles in rat and dog, together with selectivity over other trypsin-like serine proteases, identified 1f as a candidate for further evaluation.

Reference

Journal : Bioorg. Med. Chem. Lett.

Title : Sulfonamide-related conformational effects and their importance in structure-based design.

PubMed ID : 17336062

DOI : 10.1016/j.bmcl.2007.02.034

Year : 2007

Volume : 17

Issue : 10

First Page : 2931

Last Page : 2934

Authors : Senger S, Chan C, Convery MA, Hubbard JA, Shah GP, Watson NS, Young RJ.

Abstract : Structure-based design (SBD) is a challenging endeavour since even localised SAR can hardly ever be explained by the variation of just one dominating factor. Here, we present a rare example where structural information combined with ab initio calculations clearly indicate that the observed difference in biological activity is dominated by conformational effects. The learnings discussed are successfully put to the test and have the potential to be of general use as a qualitative guide in SBD efforts.

Reference

Journal : Bioorg. Med. Chem. Lett.

Title : Selective and dual action orally active inhibitors of thrombin and factor Xa.

PubMed ID : 17420122

DOI : 10.1016/j.bmcl.2007.03.080

Year : 2007

Volume : 17

Issue : 10

First Page : 2927

Last Page : 2930

Authors : Young RJ, Brown D, Burns-Kurtis CL, Chan C, Convery MA, Hubbard JA, Kelly HA, Pateman AJ, Patikis A, Senger S, Shah GP, Toomey JR, Watson NS, Zhou P.

Abstract : The synthetic entry to new classes of dual fXa/thrombin and selective thrombin inhibitors with significant oral bioavailability is described. This was achieved through minor modifications to the sulfonamide group in our potent and selective fXa inhibitor (E)-2-(5-chlorothien-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-(morpholin-4-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide and these observed activity changes have been rationalised using structural studies.

Reference

Journal : Bioorg. Med. Chem. Lett.

Title : Selective and dual action orally active inhibitors of thrombin and factor Xa.

PubMed ID : 17420122

DOI : 10.1016/j.bmcl.2007.03.080

Year : 2007

Volume : 17

Issue : 10

First Page : 2927

Last Page : 2930

Authors : Young RJ, Brown D, Burns-Kurtis CL, Chan C, Convery MA, Hubbard JA, Kelly HA, Pateman AJ, Patikis A, Senger S, Shah GP, Toomey JR, Watson NS, Zhou P.

Reference

Journal : Bioorg. Med. Chem. Lett.

Title : Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with monoaryl P4 motifs.

PubMed ID : 20006499

DOI : 10.1016/j.bmcl.2009.11.077

Year : 2010

Volume : 20

Issue : 2

First Page : 618

Last Page : 622

Authors : Kleanthous S, Borthwick AD, Brown D, Burns-Kurtis CL, Campbell M, Chaudry L, Chan C, Clarte MO, Convery MA, Harling JD, Hortense E, Irving WR, Irvine S, Pateman AJ, Patikis AN, Pinto IL, Pollard DR, Roethka TJ, Senger S, Shah GP, Stelman GJ, Toomey JR, Watson NS, West RI, Whittaker C, Zhou P, Young RJ.

Abstract : Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa inhibitors, incorporating neutral and basic monoaryl P4 groups, ultimately producing potent inhibitors with effective levels of anticoagulant activity and extended oral pharmacokinetic profiles. However, time dependant inhibition of Cytochrome P450 3A4 was a particular issue with this series.

Reference

Journal : J. Med. Chem.

Title : Factor Xa inhibitors: next-generation antithrombotic agents.

PubMed ID : 20503967

DOI : 10.1021/jm100146h

Year : 2010

Volume : 53

Issue : 17

First Page : 6243

Last Page : 6274

Authors : Pinto DJ, Smallheer JM, Cheney DL, Knabb RM, Wexler RR.

Reference

Journal : Bioorg. Med. Chem. Lett.

Title : Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with aminoindane and phenylpyrrolidine P4 motifs.

PubMed ID : 21349710

DOI : 10.1016/j.bmcl.2011.01.131

Year : 2011

Volume : 21

Issue : 6

First Page : 1582

Last Page : 1587

Authors : Young RJ, Adams C, Blows M, Brown D, Burns-Kurtis CL, Chan C, Chaudry L, Convery MA, Davies DE, Exall AM, Foster G, Harling JD, Hortense E, Irvine S, Irving WR, Jackson S, Kleanthous S, Pateman AJ, Patikis AN, Roethka TJ, Senger S, Stelman GJ, Toomey JR, West RI, Whittaker C, Zhou P, Watson NS.

Abstract : The rational design, syntheses and evaluation of potent sulfonamidopyrrolidin-2-one-based factor Xa inhibitors incorporating aminoindane and phenylpyrrolidine P4 motifs are described. These series delivered highly potent anticoagulant compounds with excellent oral pharmacokinetic profiles; however, significant time dependant P450 inhibition was an issue for the aminoindane series, but this was not observed with the phenylpyrrolidine motif, which produced candidate quality molecules with potential for once-daily oral dosing in humans.

Assay Description	Organism	Bioactivity
Inhibition of human factor Xa by fluorescence assay	Homo sapiens	4.0 nM
Inhibition of thrombin by fluorogenic assay	None	367.0 nM
Inhibition of factor 10a by fluorogenic assay	None	4.0 nM
Inhibition of thrombin by fluorogenic assay	None	367.0 nM
Inhibition of human factor 10a by fluorescence assay	Homo sapiens	4.0 nM
Inhibition of factor 10a	None	4.0 nM
Inhibition of factor 10a activity measured using bis-(CBZ-glycylglycly)-L-arginine amide fluorogenic substrate	None	4.0 nM

Cross References

Resources	Reference
ChEMBL	CHEMBL220050
DrugBank	DB07278
FDA SRS	1Y3JD5PEMS
PDB	895
SureChEMBL	SCHEMBL675586

CONTENTS

Structure
Chemical and Physical Properties