Discovery of a Novel Class of Potent and Orally Bioavailable Sphingosine 1-Phosphate Receptor 1 Antagonists

Abstract

A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists are disclosed. Our high-throughput screening campaign revealed hit 1 for which an increase in potency and mouse oral exposure was achieved with minor modifications to the chemical scaffold. In vivo efficacy revealed that at high doses compounds 12 and 15 inhibited tumor growth. Further optimization of our lead series led to the discovery of proline derivatives 37 (XL541) and 38 which had similar efficacy as our first generation analogues at significantly lower doses. Analogue 37 displayed excellent pharmacokinetics and oral exposure in multiple species.

Identification and Optimization of Benzimidazole Sulfonamides as Orally Bioavailable Sphingosine 1-Phosphate Receptor 1 Antagonists with in Vivo Activity

“…For example, changing the 4-chlorophenyl ring of 4 to a 4-fluoro or 4-cyano-substituted aryl (21 or 23) results in reduced human microsomal CL int , as does removal of the 4-substituent altogether (20). These improvements cannot be simply attributed solely to lipophilicity reduction, however, as comparably polar compounds with moieties prone to benzylic oxidation (22,26) have poorer stability.…”

“…More recently, however, disclosures of orally available, smallmolecule S1P 1 antagonists have emerged in the literature. [21][22][23] We have recently disclosed our initial efforts towards this goal, having identified a series of heterocyclic sulfonamides with submicromolar potency in a S1P 1 receptor internalization assay. 24 In this Article, we will detail our further evolution of this series of compounds, culminating in the identification of compounds (such as 46 and 47) with promising biopharmaceutical properties that elicit in vivo pharmacodynamic effects associated with antagonism of the S1P 1 receptor.…”

Discovery of a Novel Series of Potent and Orally Bioavailable Phosphoinositide 3-Kinase γ Inhibitors

“…45 Mouse liver microsome assay data, reported as the mean ± SD, was carried out as previously described. 57 2-(4-(4′-Methoxybiphenyl-3-ylsulfonyl)piperazin-1-yl)-3-(4-methoxyphenyl)pyrazine (1). To a stirred solution of 38 (896 mg, 3.00 mmol) in 1,4-dioxane (20 mL) was added HCl (5 mL, 4 N in 1,4-dioxane), and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was concentrated and used directly for the next step.…”

Structural Biology of the S1P1 Receptor

“…The first to be reported is a series of dipeptide, proline, triazole compounds that were optimized from a screening effort at Exelixis (Ibrahim et al 2012). These compounds were shown to have in vivo efficacy against tumor growth with oral administration of mice implanted with MBA-MB-231T breast adenocarcinoma xenografts.…”

“…These compounds were shown to have in vivo efficacy against tumor growth with oral administration of mice implanted with MBA-MB-231T breast adenocarcinoma xenografts. Evaluation in higher order species demonstrated promising pharmacokinetic profiles in rat, dog, and cynomolgus monkey (Ibrahim et al 2012).…”