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

Abstract

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.

A Novel Fragment Recommendation Workflow using Direct and Indirect Transfer of SAR According to Integrated Similarities of Scaffold Motifs and SAR Trends: Application to Identifying Factor Xa Inhibitors

“…The MMS R4 and R6 [36] pair yielded an MMS similarity = 0.70 (entry 6 in Table 4.a). The SAR trend of MMS R3 paralleled that of MMS R7 [37] (entry 7 in Table 4.a), although two scaffolds in this pair differed significantly from each other (scaffold similarity = 0.35, MMS similarity = 0.67). Other relationships between MMS pairs R2-R8 [38] (entry 8 in Table 4.a), R3-R9 [38] (entry 9 in Table 4.a), R2-R10 [34] (entry 10 in Table 4.a), and R2-R11 [39] (entry 11 in Table 4.a) were detected with MMS similarities = 0.67, 0.56, 0.35, and 0.28, respectively.…”

“…The chloro-substituted thiophene in MMS R6, which showed a two-generational relationship to the query MMS (Table 5.f), interacts with the S1 cavity of fXa in an X-ray structure of a 2-aminomethylphenylamine derivative [36]. Our system yielded four other related series MMS R3, R5, R7, and R8 (Tables 5.c, 5.g, and 5.h), in which the 5-chloro-2-thiopheny moieties of MMS R3 and R5, the 3-amidinophenyl moiety of MMS R7, and the 2-methylbenzofuran moiety of MMS R8 were previously modeled as S1 binding elements though computational docking simulation [34,37,38].…”

Anticoagulant therapy

“…If the prothrombinase complex responsible for rapid thrombin production is inhibited, accelerated thrombin generation is arrested (although a very low level of basal activity may persist and maintain the necessary level of coagulation [47][48][49]). This perception initiated a search for direct inhibitors able to suppress the active component of the prothrombinase complex, factor Xa [50][51][52].…”

Current trends in quantitative structure activity relationships on FXa inhibitors: Evaluation and comparative analysis

“…This effort was extended to the synthesis of benzopyrrolidinone-based aminoisoquinolines, showed in Table XVII. 89 Analyzing the data from The fact that Clog P has been used to model hydrophobicity implies that all the parts where substituents have been entered hydrophobic contacts have been made. The existence of a linear only correlation between log 1/IC 50 and Clog P suggests that the Clog P values were not great enough to establish the upper-limit for the rate of binding.…”