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

Novel inhibitors of FXIa containing an (<i>S</i>)-2-phenyl-1-(4-phenyl-1<i>H</i>-imidazol-2-yl)­ethanamine core have been optimized to provide compound <b>16b</b>, a potent, reversible inhibitor of FXIa (<i>K</i>_i = 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 <b>11a</b> and <b>11h</b> overlaid onto the X-ray crystal structure of tetrahydroquinoline <b>3</b> complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/<b>11h</b> complex. Compound <b>16b</b> was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID₉₀ for thrombus inhibition

Identification of Tricyclic Agonists of Sphingosine-1-phosphate Receptor 1 (S1P₁) Employing Ligand-Based Drug Design

Fingolimod (<b>1</b>) is the first approved oral therapy for the treatment of relapsing remitting multiple sclerosis. While the phosphorylated metabolite of fingolimod was found to be a nonselective S1P receptor agonist, agonism specifically of S1P₁ is responsible for the peripheral blood lymphopenia believed to be key to its efficacy. Identification of modulators that maintain activity on S1P₁ while sparing activity on other S1P receptors could offer equivalent efficacy with reduced liabilities. We disclose in this paper a ligand-based drug design approach that led to the discovery of a series of potent tricyclic agonists of S1P₁ with selectivity over S1P₃ and were efficacious in a pharmacodynamic model of suppression of circulating lymphocytes. Compound <b>10</b> had the desired pharmacokinetic (PK) and pharmacodynamic (PD) profile and demonstrated maximal efficacy when administered orally in a rat adjuvant arthritis model