Discovery of Milvexian, a High-Affinity, Orally Bioavailable Inhibitor of Factor XIa in Clinical Studies for Antithrombotic Therapy

被引：65

作者：

Dilger, Andrew K. ^{[1
]}

Pabbisetty, Kumar B. ^{[1
]}

Corte, James R. ^{[1
]}

De Lucca, Indawati ^{[1
]}

Fang, Tianan ^{[1
]}

Yang, Wu ^{[1
]}

Pinto, Donald J. P. ^{[1
]}

Wang, Yufeng ^{[1
]}

Zhu, Yeheng ^{[1
]}

Mathur, Arvind ^{[1
]}

Li, Jianqing ^{[1
]}

Hou, Xiaoping ^{[1
]}

Smith, Daniel ^{[1
]}

Sun, Dawn ^{[1
]}

Zhang, Huiping ^{[1
]}

Krishnananthan, Subramaniam ^{[1
]}

Wu, Dauh-Rurng ^{[1
]}

Myers, Joseph E., Jr. ^{[1
]}

Sheriff, Steven ^{[1
]}

Rossi, Karen A. ^{[1
]}

Chacko, Silvi ^{[1
]}

Zheng, Joanna J. ^{[1
]}

Galella, Michael A. ^{[1
]}

Ziemba, Theresa ^{[1
]}

Dierks, Elizabeth A. ^{[1
]}

Bozarth, Jeffrey M. ^{[1
]}

Wu, Yiming ^{[1
]}

Crain, Earl ^{[1
]}

Wong, Pancras C. ^{[1
]}

Luettgen, Joseph M. ^{[1
]}

Wexler, Ruth R. ^{[1
]}

Ewing, William R. ^{[1
]}

机构：

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 65卷 / 03期

关键词：

COAGULATION-FACTOR XIA; STRUCTURE-BASED DESIGN; SMALL-MOLECULE; THROMBUS PROPAGATION; REDUCED INCIDENCE; BLEEDING-TIME; DEFICIENCY; POTENT; PREVENTION; PYRIDINE;

D O I：

10.1021/acs.jmedchem.1c00613

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Factor XIa (FXIa) is an enzyme in the coagulation cascade thought to amplify thrombin generation but has a limited role in hemostasis. From preclinical models and human genetics, an inhibitor of FXIa has the potential to be an antithrombotic agent with superior efficacy and safety. Reversible and irreversible inhibitors of FXIa have demonstrated excellent antithrombotic efficacy without increased bleeding time in animal models (Weitz, J. I., Chan, N. C. Arterioscler. Thromb. Vasc. Biol. 2019, 39 (1), 7-12). Herein, we report the discovery of a novel series of macrocyclic FXIa inhibitors containing a pyrazole P2' moiety. Optimization of the series for (pharmacokinetic) PK properties, free fraction, and solubility resulted in the identification of milvexian (BMS- 986177/JNJ-70033093, 17, FXIa K-i= 0.11 nM) as a clinical candidate for the prevention and treatment of thromboembolic disorders, suitable for oral administration.

引用

页码：1770 / 1785

页数：16

共 45 条

[1] A synthetic heparin mimetic that allosterically inhibits factor XIa and reduces thrombosis in vivo without enhanced risk of bleeding [J].

Al-Horani, Rami A. ;

Abdelfadiel, Elsamani I. ;

Afosah, Daniel K. ;

Morla, Shravan ;

Sistla, Jyothi C. ;

Mohammed, Bassem ;

Martin, Erika J. ;

Sakagami, Masahiro ;

Brophy, Donald F. ;

Desai, Umesh R. .

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2019, 17 (12) :2110-2122

[2]

Benjamin EJ, 2019, CIRCULATION, V139, pE56, DOI [10.1161/CIR.0000000000000659, 10.1161/CIR.0000000000000746]

[3] Studies on fragment-based design of allosteric inhibitors of human factor XIa [J].

Boothello, Rio S. ;

Sankaranarayanan, Nehru Viji ;

Afosah, Daniel K. ;

Karuturi, Rajesh ;

Al-Horani, Rami A. ;

Desai, Umesh R. .

BIOORGANIC & MEDICINAL CHEMISTRY, 2020, 28 (23)

[4] Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis [J].

Bueller, Harry R. ;

Bethune, Claudette ;

Bhanot, Sanjay ;

Gailani, David ;

Monia, Brett P. ;

Raskob, Gary E. ;

Segers, Annelise ;

Verhamme, Peter ;

Weitz, Jeffrey I. .

NEW ENGLAND JOURNAL OF MEDICINE, 2015, 372 (03) :232-240

[5] Structure based design of macrocyclic factor XIa inhibitors: Discovery of cyclic P1 linker moieties with improved oral bioavailability [J].

Clark, Charles G. ;

Rossi, Karen A. ;

Corte, James R. ;

Fang, Tianan ;

Smallheer, Joanne M. ;

De Lucca, Indawati ;

Nirschl, David S. ;

Orwat, Michael J. ;

Pinto, Donald J. P. ;

Hu, Zilun ;

Wang, Yufeng ;

Yang, Wu ;

Jeon, Yoon ;

Ewing, William R. ;

Myers, Joseph E., Jr. ;

Sheriff, Steven ;

Lou, Zhen ;

Bozarth, Jeffrey M. ;

Wu, Yiming ;

Rendina, Alan ;

Harper, Timothy ;

Zheng, Joanna ;

Xin, Baomin ;

Xiang, Qian ;

Luettgen, Joseph M. ;

Seiffert, Dietmar A. ;

Wexler, Ruth R. ;

Lam, Patrick Y. S. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2019, 29 (19)

[6] Potent, Orally Bioavailable, and Efficacious Macrocyclic Inhibitors of Factor XIa. Discovery of Pyridine-Based Macrocycles Possessing Phenylazole Carboxamide P1 Groups [J].

Corte, James R. ;

Pinto, Donald J. P. ;

Fang, Tianan ;

Osuna, Honey ;

Yang, Wu ;

Wang, Yufeng ;

Lai, Amy ;

Clark, Charles G. ;

Sun, Jung-Hui ;

Rampulla, Richard ;

Mathur, Arvind ;

Kaspady, Mahammed ;

Neithnadka, Premsai Rai ;

Li, Yi-Xin Cindy ;

Rossi, Karen A. ;

Myers, Joseph E., Jr. ;

Sheriff, Steven ;

Lou, Zhen ;

Harper, Timothy W. ;

Huang, Christine ;

Zheng, Joanna J. ;

Bozarth, Jeffrey M. ;

Wu, Yiming ;

Wong, Pancras C. ;

Crain, Earl J. ;

Seiffert, Dietmar A. ;

Luettgen, Joseph M. ;

Lam, Patrick Y. S. ;

Wexler, Ruth R. ;

Ewing, William R. .

JOURNAL OF MEDICINAL CHEMISTRY, 2020, 63 (02) :784-803

[7] Macrocyclic inhibitors of Factor XIa: Discovery of alkyl-substituted macrocyclic amide linkers with improved potency [J].

Corte, James R. ;

Yang, Wu ;

Fang, Tianan ;

Wang, Yufeng ;

Osuna, Honey ;

Lai, Amy ;

Ewing, William R. ;

Rossi, Karen A. ;

Myers, Joseph E., Jr. ;

Sheriff, Steven ;

Lou, Zhen ;

Zheng, Joanna J. ;

Harper, Timothy W. ;

Bozarth, Jeffrey M. ;

Wu, Yiming ;

Luettgen, Joseph M. ;

Seiffert, Dietmar A. ;

Quan, Mimi L. ;

Wexler, Ruth R. ;

Lam, Patrick Y. S. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2017, 27 (16) :3833-3839

[8] Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker [J].

Corte, James R. ;

Fang, Tianan ;

Osuna, Honey ;

Pinto, Donald J. P. ;

Rossi, Karen A. ;

Myers, Joseph E., Jr. ;

Sheriff, Steven ;

Lou, Zhen ;

Zheng, Joanna J. ;

Harper, Timothy W. ;

Bozarth, Jeffrey M. ;

Wu, Yiming ;

Luettgen, Joseph M. ;

Seiffert, Dietmar A. ;

Decicco, Carl P. ;

Wexler, Ruth R. ;

Quan, Mimi L. .

JOURNAL OF MEDICINAL CHEMISTRY, 2017, 60 (03) :1060-1075

[9] Orally bioavailable pyridine and pyrimidine-based Factor XIa inhibitors: Discovery of the methyl N-phenyl carbamate P2 prime group [J].

Corte, James R. ;

Fang, Tianan ;

Pinto, Donald J. P. ;

Orwat, Michael J. ;

Rendina, Alan R. ;

Luettgen, Joseph M. ;

Rossi, Karen A. ;

Wei, Anzhi ;

Ramamurthy, Vidhyashankar ;

Myers, Joseph E., Jr. ;

Sheriff, Steven ;

Narayanan, Rangaraj ;

Harper, Timothy W. ;

Zheng, Joanna J. ;

Li, Yi-Xin ;

Seiffert, Dietmar A. ;

Wexler, Ruth R. ;

Quan, Mimi L. .

BIOORGANIC & MEDICINAL CHEMISTRY, 2016, 24 (10) :2257-2272

[10] Pyridine and pyridinone-based factor XIa inhibitors [J].

Corte, James R. ;

Fang, Tianan ;

Hangeland, Jon J. ;

Friends, Todd J. ;

Rendina, Alan R. ;

Luettgen, Joseph M. ;

Bozarth, Jeffrey M. ;

Barbera, Frank A. ;

Rossi, Karen A. ;

Wei, Anzhi ;

Ramamurthy, Vidhyashankar ;

Morin, Paul E. ;

Seiffert, Dietmar A. ;

Wexler, Ruth R. ;

Quan, Mimi L. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2015, 25 (04) :925-930

← 1 2 3 4 5 →