Proline bis-amides as potent dual orexin receptor antagonists

被引：63

作者：

Bergman, Jeffrey M. ^{[1
]}

Roecker, Anthony J. ^{[1
]}

Mercer, Swati P. ^{[1
]}

Bednar, Rodney A. ^{[1
]}

Reiss, Duane R. ^{[2
]}

Ransom, Richard W. ^{[2
]}

Harrell, C. Meacham ^{[2
]}

Pettibone, Douglas J. ^{[2
]}

Lemaire, Wei ^{[2
]}

Murphy, Kathy L. ^{[2
]}

Li, Chunze ^{[3
]}

Prueksaritanont, Thomayant ^{[3
]}

Winrow, Christopher J. ^{[2
]}

Renger, John J. ^{[2
]}

Koblan, Kenneth S. ^{[2
]}

Hartman, George D. ^{[1
]}

Coleman, Paul J. ^{[1
]}

机构：

[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck Res Labs, Dept Depress & Circadian Disorders, West Point, PA 19486 USA

[3] Merck Res Labs, Dept Drug Metab, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 04期

关键词：

D O I：

10.1016/j.bmcl.2008.01.001

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of OX2R/OX1R dual orexin antagonists was prepared based on a proline bis-amide identified as a screening lead. Through a combination of classical and library synthesis, potency enhancing replacements for both amide portions were discovered. N-methylation of the benzimidazole moiety within the lead structure significantly reduced P-gp susceptibility while increasing potency, giving rise to good brain penetration. A compound from this series has demonstrated in vivo central activity when dosed peripherally in a pharmacodynamic model of orexin activity. Published by Elsevier Ltd.

引用

页码：1425 / 1430

页数：6

共 50 条

[1] MEDI 320-Proline bis-amides as potent dual orexin receptor antagonists with in vivo efficacy
Roecker, Anthony J.
Bergman, Jeffrey M.
Mercer, Swati P.
Cox, Christopher D.
Breslin, Michael J.
Whitman, David B.
Albertson, Kevin B.
Doran, Scott M.
Winrow, Christopher J.
Garson, Susan L.
Fox, Steve V.
Harrell, C. Meacham
Reiss, Duane R.
Hoffman, Kristi
Anderson, Kenneth D.
Bednar, Rodney A.
Lemaire, Wei
Murphy, Kathy L.
Mahan, Elizabeth
Qiu, Julia
Li, Chunze
Prueksaritanont, Thomayant
Koblan, Ken S.
Hartman, George D.
Renger, John J.
Coleman, Paul J.
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2008, 236
[2] IDENTIFICATION OF POTENT DUAL OREXIN RECEPTOR ANTAGONISTS
Coleman, Paul J.
Schreier, John D.
Cox, Christopher D.
Breslin, Michael J.
Whitman, David B.
Roecker, Anthony J.
Bogusky, Michael J.
Bednar, Rodney A.
Lemaire, Wei
Bruno, Joseph C.
Hartman, George D.
McGaughey, Georgia B.
Reiss, Duane R.
Harrell, C. Meacham
Doran, Scott M.
Garson, Susan L.
Kraus, Richard L.
Li, Yuxing
Prueksaritanont, Thomayant
Li, Chunze
Winrow, Christopher J.
Koblan, Kenneth S.
Renger, John J.
DRUGS OF THE FUTURE, 2009, 34 : 10 - 11
[3] Bis-amido piperidine derivatives as in vitro and in vivo potent dual orexin receptor antagonists
Di Fabio, Romano
Gerrard, Philip
Porter, Rod
Stemp, Geoff
Nash, David
Branch, Clive
Massagrande, Mario
Poffe, Alessandro
Piccoli, Laura
Braggio, Simone
Ratti, Emiliangelo
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2009, 238
[4] N-Glycine-sulfonamides as potent dual orexin 1/orexin 2 receptor antagonists
Aissaoui, Hamed
Koberstein, Ralf
Zumbrunn, Cornelia
Gatfield, John
Brisbare-Roch, Catherine
Jenck, Francois
Treiber, Alexander
Boss, Christoph
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (21) : 5729 - 5733
[5] SYNTHESIS AND CYCLIZATION OF BIS-AMIDES INTO ISOQUINOLINONES
HAZAI, L
DEAK, G
ACTA CHIMICA HUNGARICA-MODELS IN CHEMISTRY, 1986, 121 (03): : 237 - 242
[6] Disubstituted piperidines as potent orexin (hypocretin) receptor antagonists
Jiang, Rong
Song, Xinyi
Bali, Purva
Smith, Anthony
Bayona, Claudia Ruiz
Lin, Li
Cameron, Michael D.
McDonald, Patricia H.
Kenny, Paul J.
Kamenecka, Theodore M.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (12) : 3890 - 3894
[7] Discovery of Highly Potent Dual Orexin Receptor Antagonists via a Scaffold-Hopping Approach
Heidmann, Bibia
Gatfield, John
Roch, Catherine
Treiber, Alexander
Tortoioli, Simone
Brotschi, Christine
Williams, Jodi T.
Bolli, Martin H.
Abele, Stefan
Sifferlen, Thierry
Jenck, Francois
Boss, Christoph
CHEMMEDCHEM, 2016, 11 (19) : 2132 - 2146
[8] Discovery and optimisation of 1-acyl-2-benzylpyrrolidines as potent dual orexin receptor antagonists
Williams, Jodi T.
Gatfield, John
Roch, Catherine
Treiber, Alexander
Jenck, Francois
Bolli, Martin H.
Brotschi, Christine
Sifferlen, Thierry
Heidmann, Bibia
Boss, Christoph
MEDCHEMCOMM, 2015, 6 (06) : 1054 - 1064
[9] Investigation of orexin-2 selective receptor antagonists: Structural modifications resulting in dual orexin receptor antagonists
Skudlarek, Jason W.
DiMarco, Christina N.
Babaoglu, Kerim
Roecker, Anthony J.
Bruno, Joseph G.
Pausch, Mark A.
O'Brien, Julie A.
Cabalu, Tamara D.
Stevens, Joanne
Brunner, Joseph
Tannenbaum, Pamela L.
Wuelfing, W. Peter
Garson, Susan L.
Fox, Steven V.
Savitz, Alan T.
Harrell, Charles M.
Gotter, Anthony L.
Winrow, Christopher J.
Renger, John J.
Kuduk, Scott D.
Coleman, Paul J.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2017, 27 (06) : 1364 - 1370
[10] Novel pyrazolo-tetrahydropyridines as potent orexin receptor antagonists
Sifferlen, Thierry
Boss, Christoph
Cottreel, Emmanuelle
Koberstein, Ralf
Gude, Markus
Aissaoui, Hamed
Weller, Thomas
Gatfield, John
Brisbare-Roch, Catherine
Jenck, Francois
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (05) : 1539 - 1542

← 1 2 3 4 5 →