Discovery of Phosphoric Acid Mono-{2-[(E/Z)-4-(3,3-dimethyl-butyrylamino)-3,5-difluorobenzoylimino]-thiazol-3-ylmethyl} Ester (Lu AA47070): A Phosphonooxymethylene Prodrug of a Potent and Selective hA2A Receptor Antagonist

被引：25

作者：

Sams, Anette G. ^{[2
]}

Mikkelsen, Gitte K. ^{[2
]}

Larsen, Mogens ^{[2
]}

Langgard, Morten ^{[1
]}

Howells, Mark E. ^{[3
]}

Schroder, Tenna J. ^{[4
]}

Brennum, Lise T. ^{[5
]}

Torup, Lars ^{[5
]}

Jorgensen, Erling B. ^{[6
]}

Bundgaard, Christoffer ^{[7
]}

Kreilgard, Mads ^{[7
]}

Bang-Andersen, Benny ^{[2
]}

机构：

[1] H Lundbeck & Co AS, Lundbeck Res Denmark, Computat Chem, DK-2500 Copenhagen, Denmark

[2] H Lundbeck & Co AS, Lundbeck Res Denmark, Med Chem Res, DK-2500 Copenhagen, Denmark

[3] H Lundbeck & Co AS, Proc Res, DK-2500 Copenhagen, Denmark

[4] H Lundbeck & Co AS, Lundbeck Res Denmark, Mol Pharmacol, DK-2500 Copenhagen, Denmark

[5] H Lundbeck & Co AS, Lundbeck Res Denmark, In Vivo Neuropharmacol, DK-2500 Copenhagen, Denmark

[6] H Lundbeck & Co AS, Lundbeck Res Denmark, Preformulat, DK-2500 Copenhagen, Denmark

[7] H Lundbeck & Co AS, Lundbeck Res Denmark, Discovery ADME, DK-2500 Copenhagen, Denmark

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 03期

关键词：

ADENOSINE A(2A) RECEPTOR; LEAD OPTIMIZATION; PROTEIN; 2-AMINO-N-PYRIMIDIN-4-YLACETAMIDES; PREDICTION; DESIGN; DRUGS;

D O I：

10.1021/jm1008659

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery and structure-activity relationship of a series of hA(2A) receptor antagonists is described. Compound 28 was selected from the series as a potent and selective compound and was shown to be efficacious in an in vivo model of Parkinson's disease. It had acceptable ADME properties; however, the low intrinsic solubility of this compound was limiting for its developability, because the oral bioavailability from dosing in suspension was significantly lower than the oral bioavailability from solution dosage. As a consequence, prodrugs of 28 were prepared with dramatically increased aqueous solubility. The prodrugs efficiently delivered 28 into systemic circulation, with no detectable levels of prodrug in plasma samples. From this investigation, we selected 32 (Lu AA47070), a phosphonooxymethylene prodrug of 28, as a drug candidate.

引用

页码：751 / 764

页数：14

共 47 条

[1]

[Anonymous], 2010, Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications

[2]

[Anonymous], 2010, MAESTR V9 0

[3]

[Anonymous], MOE VERS 2009 10

[4] Adenosine receptor antagonists: Translating medicinal chemistry and pharmacology into clinical utility [J].

Baraldi, Pier Giovanni ;

Tabrizi, Mojgan Aghazadeh ;

Gessi, Stefania ;

Borea, Pier Andrea .

CHEMICAL REVIEWS, 2008, 108 (01) :238-263

[5] Structure-Based Discovery of A2A Adenosine Receptor Ligands [J].

Carlsson, Jens ;

Yoo, Lena ;

Gao, Zhan-Guo ;

Irwin, John J. ;

Shoichet, Brian K. ;

Jacobson, Kenneth A. .

JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (09) :3748-3755

[6] 2D depiction of protein - Ligand complexes [J].

Clark, Alex M. ;

Labute, Paul .

JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2007, 47 (05) :1933-1944

[7] Synthesis of 2-amino-5-benzoyl-4-(2-furyl)thiazoles as adenosine A2A receptor antagonists [J].

Cole, Andrew G. ;

Stauffer, Tara M. ;

Rokosz, Laura L. ;

Metzger, Axel ;

Dillard, Lawrence W. ;

Zeng, Wenguang ;

Henderson, Ian .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (02) :378-381

[8] Lessons learned from marketed and investigational prodrugs [J].

Ettmayer, P ;

Amidon, GL ;

Clement, B ;

Testa, B .

JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (10) :2393-2404

[9]

FREDHOLM BB, 1994, PHARMACOL REV, V46, P143

[10] Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes [J].

Friesner, Richard A. ;

Murphy, Robert B. ;

Repasky, Matthew P. ;

Frye, Leah L. ;

Greenwood, Jeremy R. ;

Halgren, Thomas A. ;

Sanschagrin, Paul C. ;

Mainz, Daniel T. .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (21) :6177-6196

← 1 2 3 4 5 →