Orally bioavailable amine-linked macrocyclic inhibitors of factor XIa

doi:10.1016/j.bmcl.2020.126949

Bioorganic & Medicinal Chemistry Letters

Volume 30, Issue 4, 15 February 2020, 126949

https://doi.org/10.1016/j.bmcl.2020.126949 Get rights and content

Abstract

The discovery of orally bioavailable FXIa inhibitors has been a challenge. Herein, we describe our efforts to address this challenge by optimization of our imidazole-based macrocyclic series. Our optimization strategy focused on modifications to the P2 prime, macrocyclic amide linker, and the imidazole scaffold. Replacing the amide of the macrocyclic linker with amide isosteres led to the discovery of substituted amine linkers which not only maintained FXIa binding affinity but also improved oral exposure in rats. Combining the optimized macrocyclic amine linker with a pyridine scaffold afforded compounds 23 and 24 that were orally bioavailable, single-digit nanomolar FXIa inhibitors with excellent selectivity against relevant blood coagulation enzymes.

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Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The authors thank William R. Ewing, Mimi L. Quan, and Joanne M. Smallheer for critical review of this manuscript; the Department of Discovery Synthesis; Dr. Anuradha Gupta, Dr. Manivel Pitchai, and Sankara Narayanan for the synthesis of intermediates at BMS Biocon Research Center; the Department of Lead Discovery & Optimization; and Mojgan Abousleiman for in vitro work. Some of this research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User

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Cited by (4)

Studies on fragment-based design of allosteric inhibitors of human factor XIa
2020, Bioorganic and Medicinal Chemistry
Citation Excerpt :
The most often used approach of targeting hFXIa is orthosteric inhibition. This has led to the design/discovery of several heterocyclic agents and natural products as highly promising inhibitors.20–33 Prominent among these are the tetrahydroisoquinoline- (Fig. 1), pyridazine-, pyridazinone-, pyridine-, pyrimidine-and imidazole-based agents that bind in the active site of hFXIa.21,24,25,29
Human factor XIa (hFXIa) has emerged as an attractive target for development of new anticoagulants that promise higher level of safety. Different strategies have been adopted so far for the design of anti-hFXIa molecules including competitive and non-competitive inhibition. Of these, allosteric dysfunction of hFXIa’s active site is especially promising because of the possibility of controlled reduction in activity that may offer a route to safer anticoagulants. In this work, we assess fragment-based design approach to realize a group of novel allosteric hFXIa inhibitors. Starting with our earlier discovery that sulfated quinazolinone (QAO) bind in the heparin-binding site of hFXIa, we developed a group of two dozen dimeric sulfated QAOs with intervening linkers that displayed a progressive variation in inhibition potency. In direct opposition to the traditional wisdom, increasing linker flexibility led to higher potency, which could be explained by computational studies. Sulfated QAO 19S was identified as the most potent and selective inhibitor of hFXIa. Enzyme inhibition studies revealed that 19S utilizes a non-competitive mechanism of action, which was supported by fluorescence studies showing a classic sigmoidal binding profile. Studies with selected mutants of hFXIa indicated that sulfated QAOs bind in heparin-binding site of the catalytic domain of hFXIa. Overall, the approach of fragment-based design offers considerable promise for designing heparin-binding site-directed allosteric inhibitors of hFXIa.
Factor XIa Inhibitors in Anticoagulation Therapy: Recent Advances and Perspectives
2023, Journal of Medicinal Chemistry
Discovery of Milvexian, a High-Affinity, Orally Bioavailable Inhibitor of Factor XIa in Clinical Studies for Antithrombotic Therapy
2022, Journal of Medicinal Chemistry
Discovery of a High Affinity, Orally Bioavailable Macrocyclic FXIa Inhibitor with Antithrombotic Activity in Preclinical Species
2020, Journal of Medicinal Chemistry

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Orally bioavailable amine-linked macrocyclic inhibitors of factor XIa

Abstract

Graphical abstract

Section snippets

Declaration of Competing Interest

Acknowledgements

Am Heart J

Drug Discovery Today

J Med Chem

Thromb Thrombolysis

ACS Med Chem Lett

J Pharmacol Exp Ther

J Med Chem

J Med Chem

Bioorg Med Chem Lett

Bioorg Med Chem Lett

Lancet

Arterioscler Thromb Vasc Biol

N Engl J Med

J Med Chem

Eur J Pharmacol

Thromb Thrombolysis

J Med Chem

Bioorg Med Chem Lett