Discovery of BMS-753426: A Potent Orally Bioavailable Antagonist of CC Chemokine Receptor 2

被引：3

作者：

Yang, Michael G. ^{[1
]}

Xiao, Zili ^{[1
]}

Zhao, Rulin ^{[1
]}

Tebben, Andrew J. ^{[1
]}

Wang, Bei ^{[1
]}

Cherney, Robert J. ^{[1
]}

Batt, Douglas G. ^{[1
]}

Brown, Gregory D. ^{[1
]}

Cvijic, Mary Ellen ^{[1
]}

Duncia, John, V ^{[1
]}

Gallela, Michael A. ^{[1
]}

Gardner, Daniel S. ^{[1
]}

Khandelwal, Purnima ^{[1
]}

Malley, Mary F. ^{[1
]}

Pang, Jian ^{[1
]}

Rose, Anne, V ^{[1
]}

Santella, Joseph B., III ^{[1
]}

Sarjeant, Amy A. ^{[1
]}

Xu, Songmei ^{[1
]}

Mathur, Arvind ^{[1
]}

Mandlekar, Sandhya ^{[1
]}

Vuppugalla, Ragini ^{[1
]}

Zhao, Qihong ^{[1
]}

Carter, Percy H. ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Res & Dev, Princeton, NJ 08543 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2021年 / 12卷 / 06期

关键词：

CC chemokine receptor 2 (CCR2); CCR2; antagonist; Monocyte chemoattractant protein-1; Multiple sclerosis; TARGETS; BIOLOGY;

D O I：

10.1021/acsmedchemlett.1c00082

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

To improve the metabolic stability profile of BMS-741672 (1a), we undertook a structure-activity relationship study in our trisubstituted cyclohexylamine series. This ultimately led to the identification of 2d (BMS-753426) as a potent and orally bioavailable antagonist of CCR2. Compared to previous clinical candidate la, the tert-butyl amine 2d showed significant improvements in pharmacokinetic properties, with lower clearance and higher oral bioavailability. Furthermore, compound 2d exhibited improved affinity for CCRS and good activity in models of both monocyte migration and multiple sclerosis in the hCCR2 knock-in mouse. The synthesis of 2d was facilitated by the development of a simplified approach to key intermediate (4R)-9b that deployed a stereoselective reductive amination which may prove to be of general interest.

引用

下载

页码：969 / 975

页数：7

共 50 条

[31] Discovery of potent and orally bioavailable macrocyclic FXIa inhibitors
Yang, Wu
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2017, 254
[32] Discovery of BMS-193884, a potent and selective ETA receptor antagonist.
Murugesan, N
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2000, 219 : U32 - U32
[33] Discovery of potent, orally bioavailable small-molecule inhibitors of the human CCR2 receptor
Doyon, Julien
Coesemans, Erwin
Boeckx, Staf
Buntinx, Mieke
Hermans, Bart
Van Wauwe, Jean P.
Gilissen, Ron A. H. J.
De Groot, Alex H. J.
Corens, David
Van Lommen, Guy
CHEMMEDCHEM, 2008, 3 (04) : 660 - 669
[34] Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist RevealsMechanisms of Chemokine Recognition and Molecular Mimicry by HIV
Zheng, Yi
Han, Gye Won
Abagyan, Ruben
Wu, Beili
Stevens, Raymond C.
Cherezov, Vadim
Kufareva, Irina
Handel, Tracy M.
IMMUNITY, 2017, 46 (06) : 1005 - +
[35] Discovery of Potent, Orally Bioavailable Phthalazinone Bradykinin B1 Receptor Antagonists
Biswas, Kaustav
Peterkin, Tanya A. N.
Bryan, Marian C.
Arik, Leyla
Lehto, Sonya G.
Sun, Hong
Hsieh, Feng-Yin
Xu, Cen
Fremeau, Robert T.
Allen, Jennifer R.
JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (20) : 7232 - 7246
[36] Discovery and synthesis of a potent, selective and orally bioavailable EP4 receptor agonist
Young, RN
Billot, X
Han, YX
Slipetz, DA
Chauret, N
Belley, M
Metters, K
Mathieu, MC
Greig, GM
Denis, D
Girard, M
HETEROCYCLES, 2004, 64 : 437 - 446
[37] Discovery of INCB8761/PF-4136309, a Potent, Selective, and Orally Bioavailable CCR2 Antagonist
Xue, Chu-Biao
Wang, Anlai
Han, Qi
Zhang, Yingxin
Cao, Ganfeng
Feng, Hao
Huang, Taisheng
Zheng, Changsheng
Xia, Michael
Zhang, Ke
Kong, Lingquan
Glenn, Joseph
Anand, Rajan
Meloni, David
Robinson, D. J.
Shao, Lixin
Storace, Lou
Li, Mei
Hughes, Robert O.
Devraj, Rajesh
Morton, Philip A.
Rogier, D. Joseph
Covington, Maryanne
Scherle, Peggy
Diamond, Sharon
Emm, Tom
Yeleswaram, Swamy
Contel, Nancy
Vaddi, Kris
Newton, Robert
Hollis, Greg
Metcalf, Brian
ACS MEDICINAL CHEMISTRY LETTERS, 2011, 2 (12): : 913 - 918
[38] Autoimmune Pathway Blockade by a Potent Orally Bioavailable STING Antagonist
Yang, Min
Li, Hailong
Liu, Yangyang
Yao, Lili
Lin, Jing
Xie, Zhi
Zhong, Wenge
ARTHRITIS & RHEUMATOLOGY, 2023, 75 : 3141 - 3142
[39] Advances in the Discovery of CC Chemokine Receptor 2 Antagonists
Carter, Percy H.
Cherney, Robert J.
Mangion, Ian K.
ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 42, 2007, 42 : 211 - 227
[40] Discovery of a potent, orally bioavailable pyrimidine VLA-4 antagonist effective in a sheep asthma model
Semko, Christopher M.
Chen, Linda
Dressen, Darren B.
Dreyer, Mark L.
Dunn, Whitney
Farouz, Francine S.
Freedman, Stephen B.
Holsztynska, Elizabeth J.
Jefferies, Michael
Konradi, Andrei W.
Liao, Anna
Lugar, Judevin
Mutter, Linda
Pleiss, Michael A.
Quinn, Kevin P.
Thompson, Thomas
Thorsett, Eugene D.
Vandevert, Christopher
Xu, Ying-Zi
Yednock, Ted A.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (06) : 1741 - 1743

← 1 2 3 4 5 →