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...

Even though nicotinic acid (niacin) appears to have beneficial effects on human lipid profiles, niacin-induced cutaneous vasodilatation called flushing limits its remedy to patient. GPR109A is activated by niacin and mediates the anti-lipolytic effects. Based on the hypothesis that β-arrestin signaling mediates niacin-induced flushing, but not its anti-lipolytic effect, we tried to find GPR109A agonists which selectively elicit Gi-protein-biased signaling devoid of β-arrestin internalization using a β-lactamase assay. We identified a 4-(phenyl)thio-1H-pyrazole as a novel scaffold for GPR109A agonist in a high throughput screen, which has no carboxylic acid moiety known to be important for binding. While 1-nicotinoyl derivatives (5a-g, 6a-e) induced β-arrestin recruitment, 1-(pyrazin-2-oyl) derivatives were found to play as G-protein-biased agonists without GPR109A receptor internalization. The activity of compound 5a (EC50 = 45 nM) was similar to niacin (EC50 = 52 nM) and MK-6892 (EC50 = 74 nM) on calcium mobilization assay, but its activity at 10 μM on β-arrestin recruitment were around two and five times weaker than niacin and MK-6892, respectively. The development of G-protein biased GPR109A ligands over β-arrestin pathway is attainable and might be important in differentiation of pharmacological efficacy.

Protease activated receptor 1 (PAR1) has been considered as a promising antiplatelet target to prevent thrombotic cardiovascular events in patients with prior myocardial infarction or peripheral arterial diseases. Previously, we found a series of octahydroindene analogues to have high potency on PAR1 and no significant cytotoxicity but poor metabolic stability in human and rat liver microsomes. We designed and synthesized substituted analogues of octahydroindenes at C5 or C6 aiming to improvement of metabolic stability, and identified that trans-fused 5-[(tert-butoxtycarbonyl)amino]octahydroindene analogues showed improved metabolic stability with maintaining good activity on PAR1. Especially, 2-methanesulfonate 57 (IC50 = 0.006 μM; R50 = 126.3 min in human, 83.3 min in rat), sulfamate 58 (IC50 = 0.020 μM; R50 = 52.8 min in human, 106.0 min in rat), and N-(cyclopropyl)methylsufonamide 63 (IC50 = 0.010 μM; R50 = 51.4 min in human, 90.5 min in rat) exhibited excellent activity and metabolic stability both on human and rat liver microsomes, comparable to those obtained for varapaxar (IC50 = 0.0015 μM; R50 = 83.2 min in human, 32.4 min in rat). Additionally, these compounds (57, 58, and 63) represented significant efficacy (IC50 = 0.0022, 0.0062, and 0.015 μM, each) in human washed platelet aggregation (WPA) assay without cytotoxicity and CYP3A4 inhibitory activity.

Protease activated receptor 1 (PAR1) has been considered as a promising antiplatelet target to prevent thrombotic cardiovascular events in patients with prior myocardial infarction or peripheral arterial diseases. Previously, we found a series of octahydroindene analogues to have high potency on PAR1 and no significant cytotoxicity but poor metabolic stability in human and rat liver microsomes. We have designed and synthesized fused 6/5 heterobicycle analogues with octahydrocyclopenta[c]pyridine or octahydrocyclopenta[c]pyran core scaffold by the insertion of heteroatom at C5 of octahydroindene ring aiming to improvement of metabolic stability. Both heterobicycle analogues showed much more improved metabolic stability compared with octahydroindenes without remarkable decrease in activity. Compounds 22 (IC50 = 110 nM) and 33 (IC50 = 50 nM) from this series showed good activity on PAR1 with moderate metabolic stability.

Maternal embryonic leucine zipper kinase (MELK) has been implicated in various cellular processes and is highly upregulated in diverse cancers, then it is thought to be a promising anticancer target. 3‐Anilino‐1H‐pyrazolo[3,4‐b]pyridine scaffold was identified as a novel scaffold for MELK kinase inhibitors in high throughput screening (HTS). From exploration for structure–activity relationship (SAR) studies mainly by the modification of the 3 (C3), and 5‐positions (C5), 4‐(4‐methylpiperazin‐1‐yl)‐N‐{5‐[1‐(piperidin‐4‐yl)‐1H‐pyrazol‐4‐yl]‐1H‐pyrazolo[3,4‐b]pyridin‐3‐yl}benzamide (21a) was found to exhibit good activity (IC50 = 0.15 μM) on MELK as a lead in early state.