Discovery of Octahydroindenes as PAR1 Antagonists

Abstract

Octahydroindene was identified as a novel scaffold for protease activated receptor 1 (PAR1) antagonists. Herein, the 2-position (C2) was explored for structure−activity relationship (SAR) studies. Compounds 14, 19, and 23b showed IC 50 values of 1.3, 8.6, and 2.7 nM in a PAR1 radioligand binding assay, respectively, and their inhibitory activities on platelet activation were comparable to that of vorapaxar in a platelet rich plasma (PRP) aggregation assay. This series of compounds showed high potency and no significant cytotoxicity; however, the compounds were metabolically unstable in both human and rat liver microsomes. Current research efforts are focused on optimizing the compounds to improve metabolic stability and physicochemical properties as well as potency. KEYWORDS: Octahydroindene, PAR1 antagonist, PRP aggregation, antiplatelet, bleeding T he protease activated receptor 1 (PAR1) plays a critical role in thrombin mediated platelet aggregation but not in fibrin generation. It is thought to be a promising antithrombosis target with potentially less severe bleeding side effects.1,2 PAR1 is activated through proteolytic cleavage of its extracellular loop by thrombin, and the resulting new amino acid terminus (SFLLRN) intramolecularly binds to the proximally located portion of the receptor, acting as a tethered ligand to cause transmembrane signaling.3−6 Consequently, a strong interaction between PAR1 and its antagonist is required for the efficient blockage of the intramolecular binding of a tethered ligand with a very high local concentration.7−13 Vorapaxar is a very potent and virtually irreversible PAR1 antagonist with very slow receptor association and dissociation rates.14−17 Regardless the observation of an increased risk of bleeding in a phase III trial of vorapaxar on patients who had previously suffered a stroke, 18 there is still the potential to dissociate antiplatelet activity from bleeding risk.We have designed the compounds described herein using the structure of vorapaxar as a starting point to identify new PAR1 antagonists. We kept its (3-fluorophenyl)pyridine-2-vinyl moiety fixed and attempted to modify the tricyclic ring of vorapaxar. We found that a 6/5 bicycle, 19 octahydroindene could serve as a core scaffold (Figure 1). The middle 6-membered ring of vorapaxar was replaced with a 5-membered ring, and its lactone ring was opened. The 2-position (C2) of the octahydroindene was further studied to determine structure−activity relationships (SARs). In this letter, we report the SAR of this series of compounds as PAR1 antagonists and we further describe the biological and physicochemical profiles of some of the active compounds.Primarily, ketal analogues at C2 were prepared to confirm that the substitution of an octahydroindene scaffold could retain the compound's ability to inhibit PAR1. The synthesis followed the conventional procedures outlined in Scheme 1 (see the Supporting Information for details). Reductive ringopening of both cis-and trans-fused hexahydroisobenzofuran-1,3-d...

Protease activated receptor‐1 antagonist ameliorates the clinical symptoms of experimental autoimmune encephalomyelitis via inhibiting breakdown of blood–brain barrier

“…(Lee et al . ). This compound is generally not cytotoxic and shows stable concentration in human and rodent plasma.…”

“…PAR-1 antagonist SCH-530348 is considered a good clinical candidate (Vorapaxar) (Cirino and Severino 2010). To improve metabolic stability and physiochemical properties as well as potency, however, we synthesized a new PAR-1 antagonist, KC-A0590 (Lee et al 2013). KC-A0590 (octahydroindene) is designed by using the structure of SCH-530348 to identify new PAR1 antagonists, which modified the tricyclic ring of SCH-530348 and kept its (3-flurophenyl) pyridine-2-vinyl moiety fixed.…”

“…KC-A0590 (octahydroindene) is designed by using the structure of SCH-530348 to identify new PAR1 antagonists, which modified the tricyclic ring of SCH-530348 and kept its (3-flurophenyl) pyridine-2-vinyl moiety fixed. (Lee et al 2013). This compound is generally not cytotoxic and shows stable concentration in human and rodent plasma.…”

Octahydrocyclopenta[c]pyridine and octahydrocyclopenta[c]pyran analogues as a protease activated receptor 1 (PAR1) antagonist

“…Starting from 9, we prepared 6-methy-6-hydroxy 13, and 6-methyl-6-carbamate 14 compounds by published procedures (Lee et al 2013), which were found to be active on PAR1 in our previous work (Scheme 2). N-Boc was further derivatized to NH 15, N-carbamoyl 16 and N-formyl compound 17 in a straightforward method.…”

“…Previously, we identified fused 6/5 bicycle, octahydroindene as a novel scaffold for PAR1 antagonists (Lee 2011;Lee et al 2013). Although these series of compounds showed high potency and no significant cytotoxicity, they were metabolically unstable in both human and rat live microsomes.…”