Design, Synthesis, and Structure–Activity and Structure–Pharmacokinetic Relationship Studies of Novel [6,6,5] Tricyclic Fused Oxazolidinones Leading to the Discovery of a Potent, Selective, and Orally Bioavailable FXa Inhibitor

Abstract

The blood coagulation enzyme factor Xa (FXa) is a particularly promising target for anticoagulant therapy, and identification of oral small-molecule inhibitors of FXa remains a research focus. On the basis of the X-ray crystal structure of FXa and its inhibitor rivaroxaban, we designed and synthesized a series of conformationally restricted mimics containing a novel [6,6,5] tricyclic fused oxazolidinone scaffold. Intensive structure-activity relationship (SAR) and structure-pharmacokinetic relationship (SPR) studies on this new series led to the discovery of compound 11a: a highly potent, selective, direct, and orally bioavailable FXa inhibitor with excellent in vivo antithrombotic efficacy and preferable pharmacokinetic profiles. Druggability evaluation of compound 11a was undertaken and elicited positive outcomes. All results indicate that compound 11a is a promising drug candidate for the prevention and treatment of thromboembolic diseases in venous and arterial systems.

Catalytic Annulation of Epoxides with Heterocumulenes by the Indium-Tin System

“…Instead of using carbon dioxide, the cyclic adducts of epoxides with isocyanates are highly in demand [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. To effect the reaction, various catalysts have been used such as lithium halides [ 36 , 37 , 38 , 39 , 40 , 41 , 42 ], quaternary ammonium salts [ 43 , 44 ], phosphonium salt [ 45 ], AlCl 3 [ 46 ], magnesium halides [ 47 ], tetraphenylantimony iodide [ 48 , 49 , 50 ] and the chromium(Salphen) complex [ 51 ].…”

“…Cyclic carbonates are known to be efficient aprotic polar solvents [ 10 , 11 , 12 ], electrolytes in lithium ion batteries [ 13 , 14 ] and materials for producing polycarbonates [ 15 ]. Instead of the products from carbon dioxide, the cyclic adducts of epoxides with isocyanates such as 2-oxazolidinones [ 16 , 17 ] are important biologically-active compounds [ 18 , 19 , 20 , 21 , 22 ] and synthetic intermediates such as precursors of amino alcohols and chiral auxiliaries [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. We present here a simple, easily available catalyst, the indium-tin system, and provide the environmentally-benign process to annulated adducts under mild conditions.…”

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

“…Yang and co-workers employed Pd-catalyzed N-arylation of lactams to arrive at a potent anticoagulant drug candidate ( 393 , Scheme 92 a). 325 Previously, a series of cyclic amides had been successfully combined with tricyclic oxazolidinone 391 in the presence of Pd 2 (dba) 3 , L7 , and Cs 2 CO 3 ; the δ-lactam 392 gave rise to the most active compound. The Hergenrother group developed an efficient multistep route to prepare the potential anticancer agent DNQ and study its mechanism of action ( Scheme 92 b).…”

Synthesis and evaluation of anthranilamide-based derivatives as FXa inhibitors

“…Up to date, three oral direct FXa inhibitors such as Rivaroxaban have been approved to treat the venous thrombosis in clinics and several other candidates were in the variant stages of clinical studies or biological testing (the structures of three approved drugs were in Figure 1) [7]. However, these three medicines still possess specific obstacles in clinical utility, such as risk of bleeding (including intracranial bleeding, gastrointestinal bleeding, epistaxis and other fatal bleeds), no antidote and higher incidence of thromboembolic events after ceasing treatment [8]. Therefore, the development of novel antithrombotic drugs is still attracted many attention for unmet clinical demand.…”