Optimization of Novel Antagonists to the Neurokinin-3 Receptor for the Treatment of Sex-Hormone Disorders (Part II)

被引：43

作者：

Hoveyda, Hamid R. ^{[1
]}

Fraser, Graeme L. ^{[1
]}

Dutheuil, Guillaume ^{[1
]}

El Bousmaqui, Mohamed ^{[1
]}

Korac, Julien ^{[1
]}

Lenoir, Francois ^{[1
]}

Lapin, Alexey ^{[1
]}

Noel, Sophie ^{[1
]}

机构：

[1] Euroscreen SA, B-6041 Gosselies, Belgium

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2015年 / 6卷 / 07期

关键词：

NK3; antagonist; triazolopiperazine; neurokinin B; LH; FSH; GnRH; PLASMA-PROTEIN BINDING; GNRH;

D O I：

10.1021/acsmedchemlett.5b00117

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Further lead optimization on N-acyl-triazolopiperazine antagonists to the neurokinin-3 receptor (NK3R) based on the concurrent improvement in bioactivity and ligand lipophilic efficiency (LLE) is reported. Overall, compound 3 (LLE > 6) emerged as the most efficacious in castrated rat and monkey to lower plasma LH, and it displayed the best off-target safety profile that led to its clinical candidate nomination for the treatment of sex-hormone disorders.

引用

页码：736 / 740

页数：5

共 18 条

[1] Progress in the development of neurokinin 3 modulators for the treatment of schizophrenia: molecule development and clinical progress [J].

Dawson, Lee A. ;

Porter, Roderick A. .

FUTURE MEDICINAL CHEMISTRY, 2013, 5 (13) :1525-1546

[2] Normosmic Congenital Hypogonadotropic Hypogonadism Due to TAC3/TACR3 Mutations: Characterization of Neuroendocrine Phenotypes and Novel Mutations [J].

Francou, Bruno ;

Bouligand, Jerome ;

Voican, Adela ;

Amazit, Larbi ;

Trabado, Severine ;

Fagart, Jerome ;

Meduri, Geri ;

Brailly-Tabard, Sylvie ;

Chanson, Philippe ;

Lecomte, Pierre ;

Guiochon-Mantel, Anne ;

Young, Jacques .

PLOS ONE, 2011, 6 (10)

[3]

Fraser G. L., ENDOCRINOLOGY UNPUB

[4] VN/14-1 induces ER stress and autophagy in HP-LTLC human breast cancer cells and has excellent oral pharmacokinetic profile in female Sprague Dawley rats [J].

Godbole, Abhijit M. ;

Ramalingam, Senthilmurugan ;

Ramamurthy, Vidya P. ;

Khandelwal, Aakanksha ;

Bruno, Robert D. ;

Upreti, Vijay V. ;

Gediya, Lalji K. ;

Purushottamachar, Puranik ;

Mbatia, Hannah W. ;

Addya, Sankar ;

Ambulos, Nicholas ;

Njar, Vincent C. O. .

EUROPEAN JOURNAL OF PHARMACOLOGY, 2014, 734 :98-104

[5] Bioactivation Potential of Thiophene-Containing Drugs [J].

Gramec, Darja ;

Masic, Lucija Peterlin ;

Dolenc, Marija Sollner .

CHEMICAL RESEARCH IN TOXICOLOGY, 2014, 27 (08) :1344-1358

[6] The role of ligand efficiency metrics in drug discovery [J].

Hopkins, Andrew L. ;

Keserue, Gyoergy M. ;

Leeson, Paul D. ;

Rees, David C. ;

Reynolds, Charles H. .

NATURE REVIEWS DRUG DISCOVERY, 2014, 13 (02) :105-121

[7] Discovery and Optimization of Novel Antagonists to the Human Neurokinin-3 Receptor for the Treatment of Sex-Hormone Disorders (Part I) [J].

Hoveyda, Hamid R. ;

Fraser, Graeme L. ;

Roy, Marie-Odile ;

Dutheuil, Guillaume ;

Batt, Frederic ;

El Bousmaqui, Mohamed ;

Korac, Julien ;

Lenoir, Francois ;

Lapin, Alexey ;

Noel, Sophie ;

Blanc, Sebastien .

JOURNAL OF MEDICINAL CHEMISTRY, 2015, 58 (07) :3060-3082

[8] A rational chemical intervention strategy to circumvent bioactivation liabilities associated with a nonpeptidyl thrombopoietin receptor agonist containing a 2-amino-4-arylthiazole motif [J].

Kalgutkar, Amit S. ;

Driscoll, James ;

Zhao, Sabrina X. ;

Walker, Gregory S. ;

Shepard, Richard M. ;

Soglia, John R. ;

Atherton, James ;

Yu, Linning ;

Mutlib, Abdul E. ;

Munchhof, Michael J. ;

Reiter, Lawrence A. ;

Jones, Christopher S. ;

Doty, Johnathan L. ;

Trevena, Kristen A. ;

Shaffer, Christopher L. ;

Ripp, Sharon L. .

CHEMICAL RESEARCH IN TOXICOLOGY, 2007, 20 (12) :1954-1965

[9]

Kerns EH, 2008, DRUG-LIKE PROPERTIES: CONCEPTS, STRUCTURE DESIGN AND METHODS, P122, DOI 10.1016/B978-012369520-8.50011-5

[10] Predicting plasma protein binding of drugs:: a new approach [J].

Kratochwil, NA ;

Huber, W ;

Müller, F ;

Kansy, M ;

Gerber, PR .

BIOCHEMICAL PHARMACOLOGY, 2002, 64 (09) :1355-1374

← 1 2 →