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

被引：20

作者：

Corte, James R. ^{[1
]}

Fang, Tianan ^{[1
]}

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

Orwat, Michael J. ^{[1
]}

Rendina, Alan R. ^{[1
]}

Luettgen, Joseph M. ^{[1
]}

Rossi, Karen A. ^{[1
]}

Wei, Anzhi ^{[1
]}

Ramamurthy, Vidhyashankar ^{[1
]}

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

Sheriff, Steven ^{[1
]}

Narayanan, Rangaraj ^{[1
]}

Harper, Timothy W. ^{[1
]}

Zheng, Joanna J. ^{[1
]}

Li, Yi-Xin ^{[1
]}

Seiffert, Dietmar A. ^{[1
]}

Wexler, Ruth R. ^{[1
]}

Quan, Mimi L. ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Res & Dev, POB 5400, Princeton, NJ 08543 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2016年 / 24卷 / 10期

关键词：

Factor XIa; FXIa; Thrombosis; Activated partial thromboplastin time aPTT; COAGULATION-FACTOR XIA; SMALL-MOLECULE; BIOLOGICAL EVALUATION; THROMBUS PROPAGATION; REDUCED INCIDENCE; CAROTID-ARTERY; BLEEDING-TIME; IN-VITRO; DEFICIENCY; DESIGN;

D O I：

10.1016/j.bmc.2016.03.062

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Pyridine-based Factor XIa (FXIa) inhibitor (S)-2 was optimized by modifying the P2 prime, P1, and scaffold regions. This work resulted in the discovery of the methyl N-phenyl carbamate P2 prime group which maintained FXIa activity, reduced the number of H-bond donors, and improved the physicochemical properties compared to the amino indazole P2 prime moiety. Compound (S)-17 was identified as a potent and selective FXIa inhibitor that was orally bioavailable. Replacement of the basic cyclohexyl methyl amine P1 in (S)-17 with the neutral p-chlorophenyltetrazole P1 resulted in the discovery of (S)-24 which showed a significant improvement in oral bioavailability compared to the previously reported imidazole (S)-23. Additional improvements in FXIa binding affinity, while maintaining oral bioavailability, was achieved by replacing the pyridine scaffold with either a regioisomeric pyridine or pyrimidine ring system. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：2257 / 2272

页数：16

共 55 条

[1] Designing Allosteric Inhibitors of Factor XIa. Lessons from the Interactions of Sulfated Pentagalloylglucopyranosides [J].

Al-Horani, Rami A. ;

Desai, Umesh R. .

JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (11) :4805-4818

[2] THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].

BAILEY, S .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1994, 50 :760-763

[3]

BAIOCCHI L, 1978, SYNTHESIS-STUTTGART, P633

[4]

Bane CE, 2014, HEMOSTASIS AND THROMBOSIS: PRACTICAL GUIDELINES IN CLINICAL MANAGEMENT, P71

[5] Factor XI as a target for antithrombotic therapy [J].

Bane, Charles E., Jr. ;

Gailani, David .

DRUG DISCOVERY TODAY, 2014, 19 (09) :1454-1458

[6] Refinement of severely incomplete structures with maximum likelihood in BUSTER-TNT [J].

Blanc, E ;

Roversi, P ;

Vonrhein, C ;

Flensburg, C ;

Lea, SM ;

Bricogne, G .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2004, 60 :2210-2221

[7] Clavatadine A, a natural product with selective recognition and irreversible inhibition of factor XIa [J].

Buchanan, Malcolm S. ;

Carroll, Anthony R. ;

Wessling, Deborah ;

Jobling, Michael ;

Avery, Vicky M. ;

Davis, Rohan A. ;

Feng, Yunjiang ;

Xue, Yafeng ;

Oster, Linda ;

Fex, Tomas ;

Deinum, Johanna ;

Hooper, John N. A. ;

Quinn, Ronald J. .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (12) :3583-3587

[8] 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

[9] LARGE-SCALE SYNTHESIS OF 4-ETHYLPYRIMIDINE [J].

BUTTERS, M .

JOURNAL OF HETEROCYCLIC CHEMISTRY, 1992, 29 (05) :1369-1370

[10]

Colman RW., 1994, HEMOSTASIS THROMBOSI, V3rd

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