Design, Synthesis, and Structure-Activity Relationships of Pyridine-Based Rho Kinase (ROCK) Inhibitors

被引：51

作者：

Green, Jeremy ^{[1
]}

Cao, Jingrong ^{[1
]}

Bandarage, Upul K. ^{[1
]}

Gao, Huai ^{[1
]}

Court, John ^{[1
]}

Marhefka, Craig ^{[1
]}

Jacobs, Marc ^{[1
]}

Taslimi, Paul ^{[1
]}

Newsome, David ^{[1
]}

Nakayama, Tomoko ^{[1
]}

Shah, Sundeep ^{[2
]}

Rodems, Steve ^{[2
]}

机构：

[1] Vertex Pharmaceut Inc, Boston, MA 02210 USA

[2] Vertex Pharmaceut Inc, San Diego, CA 92121 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 12期

关键词：

PROTEIN-KINASE; ERECTILE DYSFUNCTION; HYPERTENSION; FASUDIL; OPTIMIZATION; DISCOVERY; GLAUCOMA;

D O I：

10.1021/acs.jmedchem.5b00424

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The Rho kinases (ROCK1 and ROCK2) are highly homologous serine/threonine kinases that act on substrates associated with cellular motility, morphology, and contraction and are of therapeutic interest in diseases associated with cellular migration and contraction, such as hypertension, glaucoma, and erectile dysfunction. Beginning with compound 4, an inhibitor of ROCK1 identified through high-throughput screening, systematic exploration of SAR, and application of structure-based design, led to potent and selective ROCK inhibitors. Compound 37 represents significant improvements in inhibition potency, kinase selectivity, and CYP inhibition and possesses pharmacokinetics suitable for in vivo experimentation.

引用

页码：5028 / 5037

页数：10

共 50 条

[1] ROCK inhibitors 3: Design, synthesis and structure-activity relationships of 7-azaindole-based Rho kinase (ROCK) inhibitors
Bandarage, Upul K.
Cao, Jingrong
Come, Jon H.
Court, John J.
Gao, Huai
Jacobs, Marc D.
Marhefka, Craig
Nanthakumar, Suganthi
Green, Jeremy
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2018, 28 (15) : 2622 - 2626
[2] ROCK inhibitors 4: Structure-activity relationship studies of 7-azaindole-based rho kinase (ROCK) inhibitors
Bandarage, Upul K.
Court, John
Gao, Huai
Nanthakumar, Suganthini
Come, Jon H.
Giroux, Simon
Green, Jeremy
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2021, 33
[3] Design, synthesis and structure-activity relationships of novel biarylamine-based Met kinase inhibitors
Williams, David K.
Chen, Xiao-Tao
Tarby, Christine
Kaltenbach, Robert
Cai, Zhen-Wei
Tokarski, John S.
An, Yongmi
Sack, John S.
Wautlet, Barri
Gullo-Brown, Johnni
Henley, Benjamin J.
Jeyaseelan, Robert
Kellar, Kristen
Manne, Veeraswamy
Trainor, George L.
Lombardo, Louis J.
Fargnoli, Joseph
Borzilleri, Robert M.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (09) : 2998 - 3002
[4] Design, synthesis, and structure-activity relationships of tetrahydroquinoline-based farnesyltransferase inhibitors
Lombardo, LJ
Camuso, A
Clark, J
Fager, K
Gullo-Brown, J
Hunt, JT
Inigo, I
Kan, D
Koplowitz, B
Lee, F
McGlinchey, K
Qian, LG
Ricca, C
Rovnyak, G
Traeger, S
Tokarski, J
Williams, DK
Wu, LI
Zhao, YF
Manne, V
Bhide, RS
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (07) : 1895 - 1899
[5] Design, synthesis and structure-activity relationships of carbohydrazide based cathepsin K inhibitors
Thompson, SK
Tomaszek, TA
Tew, DG
Levy, MA
Smith, WW
Zhao, B
Janson, CA
D'Alessio, KJ
McQueney, MS
DesJarlais, RL
Abdel-Meguid, SS
Veber, DF
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 1998, 216 : U287 - U287
[6] Design, synthesis and structure-activity relationships of novel ALS inhibitors
Ren, TR
Yang, HW
Gao, X
Yang, XL
Zhou, JJ
Cheng, FH
PEST MANAGEMENT SCIENCE, 2000, 56 (03) : 218 - 226
[7] Synthesis and Structure-Activity Relationships of Benzothienothiazepinone Inhibitors of Protein Kinase D
Bravo-Altamirano, Karla
George, Kara M.
Frantz, Marie-Celine
LaValle, Courtney R.
Tandon, Manuj
Leimgruber, Stephanie
Sharlow, Elizabeth R.
Lazo, John S.
Wang, Q. Jane
Wipf, Peter
ACS MEDICINAL CHEMISTRY LETTERS, 2011, 2 (02): : 154 - 159
[8] Design, synthesis, and structure-activity relationships of a series of urea based MMP inhibitors.
Chen, JJ
Lin, XH
Browner, MF
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 1999, 217 : U1214 - U1214
[9] Design, synthesis and structure-activity relationships of benzoxazinone-based factor Xa inhibitors
Huang, WR
Zhang, PL
Zuckett, JF
Wang, LY
Woolfrey, J
Song, YH
Jia, ZZJ
Clizbe, LA
Su, T
Tran, K
Huang, B
Wong, P
Sinha, U
Park, G
Reed, A
Malinowski, J
Hollenbach, SJ
Scarborough, RM
Zhu, BY
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (03) : 561 - 566
[10] Pyrazole-Based Acid Ceramidase Inhibitors: Design, Synthesis, and Structure-Activity Relationships
Diamanti, Eleonora
Bottegoni, Giovanni
Goldoni, Luca
Realini, Natalia
Pagliuca, Chiara
Bertozzi, Fabio
Piomelli, Daniele
Pizzirani, Daniela
SYNTHESIS-STUTTGART, 2016, 48 (17): : 2739 - 2756

← 1 2 3 4 5 →