Joanne M. Smallheer

Tetrahydroquinoline derivatives as potent and selective factor XIa inhibitors.

Antithrombotic agents that are inhibitors of factor XIa (FXIa) have the potential to demonstrate robust efficacy with a low bleeding risk profile. Herein, we describe a series of tetrahydroquinoline (THQ) derivatives as FXIa inhibitors. Compound 1 was identified as a potent and selective tool compound for proof of concept studies. It exhibited excellent antithrombotic efficacy in rabbit thrombosis models and did not prolong bleeding times. This demonstrates proof of concept for the FXIa mechanism in animal models with a reversible, small molecule inhibitor.

Phenylimidazoles as Potent and Selective Inhibitors of Coagulation Factor XIa with in Vivo Antithrombotic Activity

Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (Ki = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg kg(-1) h(-1)). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlaid onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID90 for thrombus inhibition.

Synthesis of 1,5-dimethyl-1,4-dihydropyrrolo[3,4-b]-pyrrol-6(5H)-one by intramolecular Diels-Alder reaction to the imidazole nucleus.

Abstract N-Methyl-N-propargylimidazole-5-carboxamide undergoes thermal intramolecular Diels-Alder reaction to give the title compound. A related reaction of the corresponding sydnone system is also described.

Intramolecular diels-alder reactions of isoquinoline-1-carboxamides

Abstract N -methyl- N -propargyl and N -methyl- N -allylisoquinoline-1-carboxamides undergo facile intramolecular Diels-Alder reactions to give fused N -methyl-γ-lactams.