Oral Thrombin Inhibitors: Challenges and Progress

Kimball, S. David

doi:10.1007/978-3-642-59942-2_13

Cited by 6 publications

(6 citation statements)

References 128 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thrombin has several procoagulant functions that include the activation of platelets, the feedback activation of other coagulation factors, and the conversion of fibrinogen to insoluble fibrin clots. Small molecule thrombin inhibitors have been intensely investigated . More recently, direct inhibition of fXa has emerged as an attractive strategy for the discovery of novel antithrombotic agents. , Since fXa inhibitors specifically affect coagulation, but not platelet function, this mechanism may be anticipated to have less potential to increase the risk of abnormal bleeding relative to thrombin inhibitors and antiplatelet agents.…”

Section: Introductionmentioning

confidence: 99%

“…Small molecule thrombin inhibitors have been intensely investigated . More recently, direct inhibition of fXa has emerged as an attractive strategy for the discovery of novel antithrombotic agents. , Since fXa inhibitors specifically affect coagulation, but not platelet function, this mechanism may be anticipated to have less potential to increase the risk of abnormal bleeding relative to thrombin inhibitors and antiplatelet agents. A comparison between hirudin (a thrombin inhibitor) and tick anticoagulant peptide (TAP, an fXa inhibitor) suggests that inhibition of fXa may result in less bleeding risk, leading to a more favorable safety/efficacy ratio …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of 1-[3-(Aminomethyl)phenyl]-N-[3-fluoro-2‘-(methylsulfonyl)- [1,1‘-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a Highly Potent, Selective, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa

et al. 2001

View full text Add to dashboard Cite

Factor Xa (fXa) plays a critical role in the coagulation cascade, serving as the point of convergence of the intrinsic and extrinsic pathways. Together with nonenzymatic cofactor Va and Ca2+ on the phospholipid surface of platelets or endothelial cells, factor Xa forms the prothrombinase complex, which is responsible for the proteolysis of prothrombin to catalytically active thrombin. Thrombin, in turn, catalyzes the cleavage of fibrinogen to fibrin, thus initiating a process that ultimately leads to clot formation. Recently, we reported on a series of isoxazoline and isoxazole monobasic noncovalent inhibitors of factor Xa which show good potency in animal models of thrombosis. In this paper, we wish to report on the optimization of the heterocyclic core, which ultimately led to the discovery of a novel pyrazole SN429 (2b; fXa K(i) = 13 pM). We also report on our efforts to improve the oral bioavailability and pharmacokinetic profile of this series while maintaining subnanomolar potency and in vitro selectivity. This was achieved by replacing the highly basic benzamidine P1 with a less basic benzylamine moiety. Further optimization of the pyrazole core substitution and the biphenyl P4 culminated in the discovery of DPC423 (17h), a highly potent, selective, and orally active factor Xa inhibitor which was chosen for clinical development.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery of 1-[3-(Aminomethyl)phenyl]-N-[3-fluoro-2‘-(methylsulfonyl)- [1,1‘-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a Highly Potent, Selective, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa

et al. 2001

View full text Add to dashboard Cite

show abstract

“…In recent years, a number of very potent and selective active-site directed thrombin inhibitors have been designed using arginine or benzamidine as an active site recognition element~Edmunds & Rapundalo, 1996;Wiley & Fisher, 1997;Kaiser, 1998;Menear, 1998;Sanderson & Naylor-Olsen, 1998;Uzan, 1998;Want et al, 1998;Kimball, 1999!. Crystal structures of the complexes between thrombin and a number of these inhibitors, including the arginal tripeptide d-Phe-Pro-Arg-H and its related analogs, NAPAP, Ar-gatroban~MD-805!, and cyclotheonamide A, have been deter-mined~Bode et al, 1989deter-mined~Bode et al, , 1992Banner & Hadvary, 1991;Chirgadze et al, 1992;Maryanoff et al, 1993!. All have a similar binding orientation, namely an antiparallel beta-sheet arrangement between the inhibitor and enzyme that is stabilized by hydrogen bonds to Gly216.…”

mentioning

confidence: 99%

The crystal structures of human α‐thrombin complexed with active site‐directed diamino benzo[b] thiophene derivatives: A binding mode for a structurally novel class of inhibitors

et al. 2000

View full text Add to dashboard Cite

The crystal structures of four active site-directed thrombin inhibitors, 1-4, in a complex with human alpha-thrombin have been determined and refined at up to 2.0 A resolution using X-ray crystallography. These compounds belong to a structurally novel family of inhibitors based on a 2,3-disubstituted benzo[b]thiophene structure. Compared to traditional active-site directed inhibitors, the X-ray crystal structures of these complexes reveal a novel binding mode. Unexpectedly, the lipophilic benzo[b]thiophene nucleus of the inhibitor appears to bind in the S1 specificity pocket. At the same time, the basic amine of the C-3 side chain of the inhibitor interacts with the mostly hydrophobic proximal, S2, and distal, S3, binding sites. The second, basic amine side chain at C-2 was found to point away from the active site, occupying a location between the S1 and S1' sites. Together, the aromatic rings of the C-2 and C-3 side chains sandwich the indole ring of Trp60D contained in the thrombin S2 insertion loop defined by the sequence "Tyr-Pro-Pro-Trp." [The thrombin residue numbering used in this study is equivalent to that reported for chymotrypsinogen (Hartley BS, Shotton DM, 1971, The enzymes, vol. 3. New York: Academic Press. pp 323-373).] In contrast to the binding mode of more classical thrombin inhibitors (D-Phe-Pro-Arg-H, NAPAP, Argatroban), this novel class of benzo[b]thiophene derivatives does not engage in hydrogen bond formation with Gly216 of the thrombin active site. A detailed analysis of the three-dimensional structures not only provides a clearer understanding of the interaction of these agents with thrombin, but forms a foundation for rational structure-based drug design. The use of the data from this study has led to the design of derivatives that are up to 2,900-fold more potent than the screening hit 1.

show abstract

“…However, there is also interest in developing FXa inhibitors for the treatment or prevention of chronic maladies, such as deep-vein thrombosis. While there are a limited number of orally active FXa inhibitors, or even antithrombins, it is readily apparent from the published SAR that oral activity is limited in part by highly basic P1 substituents . In an attempt to address this issue, we prepared a number of benzoxazinones ( 1m and 1o − 1q ) containing P1 groups with modest p K a (10 ± 2) as calculated from commercial software .…”

Section: Resultsmentioning

confidence: 99%

Rational Design, Synthesis, and Biological Activity of Benzoxazinones as Novel Factor Xa Inhibitors

et al. 2000

View full text Add to dashboard Cite

Inappropriate thrombus formation within blood vessels is the leading cause of mortality in the industrialized world. Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in the blood coagulation cascade and represents an attractive target for anticoagulant drug development. From a high-throughput in vitro mass screen of our chemical library, we identified 4-[5-[(2R,6S)-2, 6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-2-phenyl-2H-1, 4-benzoxazin-3(4H)-one (1a) as an inhibitor of FXa with an IC(50) of 27 microM. Through a combination of SAR studies and molecular modeling, we synthesized 3-(4-[5-[(2R,6S)-2, 6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-yl)-1-benzenecarboximidamide (1n) which was a potent FXa inhibitor with an IC(50) of 3 nM. This compound exhibited high selectivity for FXa over other related serine proteases and was efficacious when dosed intravenously in rabbit and dog antithrombotic models.

show abstract

Oral Thrombin Inhibitors: Challenges and Progress

Cited by 6 publications

References 128 publications

Discovery of 1-[3-(Aminomethyl)phenyl]-N-[3-fluoro-2‘-(methylsulfonyl)- [1,1‘-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a Highly Potent, Selective, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa

Discovery of 1-[3-(Aminomethyl)phenyl]-N-[3-fluoro-2‘-(methylsulfonyl)- [1,1‘-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a Highly Potent, Selective, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa

The crystal structures of human α‐thrombin complexed with active site‐directed diamino benzo[b] thiophene derivatives: A binding mode for a structurally novel class of inhibitors

Rational Design, Synthesis, and Biological Activity of Benzoxazinones as Novel Factor Xa Inhibitors

Contact Info

Product

Resources

About