3-(1H-Imidazol-2-Yl)-2,3,8,8a-Tetrahydroindolizin-5(1H)-One Derivatives are Useful as Factor Xia Inhibitors and Their Preparation

1. INTRODUCTION

1.1. Main Compound Classes

Summary:

Thromboembolic diseases remain the leading cause of death in developed countries despite the availability of anticoagulants such as warfarin (COUMADIN^®), heparin, low molecular weight heparin (LMWH), and synthetic pentasaccharides and antiplatelet agents such as aspirin and clopidogrel (PLAVIX^®) [1-3]. The oral anticoagulant warfarin inhibits the post-translational maturation of coagulation factors VII, IX, X, and prothrombin and has proven effective in both venous and arterial thrombosis. However, its usage is limited due to its narrow therapeutic index with respect to bleeding safety, slow onset of therapeutic effects, numerous dietary and drug-drug interactions, and a need for monitoring and dose adjustment [1-3].

Novel oral anticoagulants directly targeting either thrombin or factor Xa, e.g., dabigatran, apixaban, betrixaban, edoxaban, rivaroxaban, have been approved for both venous and arterial indications. However, the risk of bleeding is not completely eliminated and can be as high as 2-3% per year in patients with atrial fibrillation [4-10]. Thus, discovering and developing safe and efficacious oral anticoagulants with minimal impact on hemostasis for the prevention and treatment of a wide range of thromboembolic disorders has become increasingly important [9-12].

2. METHODS

The patent claims a new class of Factor XIa FXIa inhibitors belonging to the chemical category of 3-(1H-Imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one. Key structures are provided in Fig. (1). Key definitions of the general structure are provided below.

Fig. (1).

Key derivatives 3-(1H-Imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one reported as FXIa inhibitor in this patent.

Definitions:

More details are in the patent.

R¹ = Halogen, hydroxy, C_1-4alkyl, fluorinated C_1-4alkyl, C_1-4alkoxy, fluorinated C_1-4alkoxy, cyano, nitro, -NR^AR^B, - C(O)-C_1-4alkyl, C_3-6cycloalkyl, phenyl and 5 to 6 membered heterocyclyl

A = integer from 0 to 3

R² = Chloro, fluoro, methyl, and methoxy

R^A /R^B = Hydrogen and halogen; alternatively, R^A and R^B are taken together with the carbon atom to which they are bound to form oxo

R^c = Hydrogen and C_1-4alkyl

R^D = Hydrogen, C_1-4alkyl and C_1-4alkoxy

R^E = Hydrogen and C_1-4alkyl

Q = Can be:

3. RESULT & DISCUSSION

Biological Assay:

A fluorescence intensity (FLINT) based assay was used to evaluate the inhibition of factor Xla by the molecules presented in the patent. The peptide substrate, 5Fam-KLTRAETV-K5Tamra was chosen based on the FXI sequence. Similar assay was used to determine the inhibition of the human kallikrein enzyme, a similar enzyme to factor XIa.

Biological Data:

Potency (IC₅₀) of the inhibitors against both factor XIa, as well as kallikrein, was provided as IC₅₀ values, which were determined by FLINT assay. Table 1 provides representative examples.

Table 1.

Inhibition profiles of key structures against human factor XIa and the closely related enzyme kallikrein.

Inhibitor	FXIa IC50 (nM)	Kallikrein IC50 (nM)
6	0.6	6.6
34	0.6	32.8
40	0.8	6.4
54	0.8	67.9
58	0.7	49.2
61	0.5	44.4

CONCLUSION

Factor XIa is currently the most targeted protease in the coagulation cascade for developing effective anticoagulants that are not associated with bleeding risk [7-12]. The preparation of factor XIa inhibitors of 3-(1H-Imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one derivative has been described. Key inhibitors were evaluated for their ability to inhibit both factor XIa and kallilkrein. The potential of the claimed inhibitors and their pharmacokinetics are yet to be determined in appropriate animal models.