Discovery of DS44470011: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia.

Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We identified a pyrimidine core with HIF-PHD inhibitory activity based on scaffold hopping of FG-2216 using crystal structures of HIF-PHD2 in complex with compound. By optimizing the substituents at the 2- and 6- positions of the pyrimidine core, we discovered DS44470011, which improves the effectiveness of erythropoietin (EPO) release in cells. Oral administration of DS44470011 to cynomolgus monkeys increased plasma EPO levels.

Discovery of DS-1093a: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia.

Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We discovered DS44470011 in our previous study, which showed potent in vitro activity and in vivo efficacy based on HIF-PHD inhibition. However, DS44470011 was also found to exert genotoxic effects. By converting the biphenyl structure, which is suspected to be the cause of this genotoxicity, to a 1-phenylpiperidine structure, we were able to avoid genotoxicity and further improve the in vitro activity and in vivo efficacy. Furthermore, through the optimization of pyrimidine derivatives, we discovered DS-1093a, which has a wide safety margin with potent in vitro activity and an optimal pharmacokinetic profile. DS-1093a achieved an increase in hemoglobin levels in an adenine-induced rat model of chronic kidney disease after its continuous administration for 4 days.

Hydrated Phospholipid Polymer Gel-Like Layer for Increased Durability of Orthopedic Bearing Surfaces.

Recently, traditional strategies for manipulating orthopedic bearing substrates have attempted to improve their wear resistance by adjusting polyethylene substrate through cross-linking and antioxidant blending. However, further research is required on the substrate, as well as the surface focused on the structure and role of articular cartilage. We therefore develop an orthopedic bearing surface comprising a nanometer-scale hydrated gel-like layer by grafting highly hydrophilic poly(2-methacryloyloxyethyl phosphorylcholine), with the aim of mimicking the lubrication mechanism of articular cartilage, and investigate its surface characteristics, bulk characteristics, and behavior under load bearing conditions upon accelerated aging. Neither the hydrophilicity nor lubricity of the gel-like surface was influenced by accelerated aging; instead, high stability was revealed, even under strong oxidation conditions. The characteristics of the hydrated gel-like surface potentiated the wear resistance of the cross-linked polyethylene liner, irrespective of accelerated aging. These results suggest that the hydrated gel-like surface enhances the longevity of cross-linked polyethylene bearings even under load-bearing conditions. Furthermore, the inflection point on the time series of wear can be a suitable indicator of the durability of the life-long protectant. In conclusion, the hydrated gel-like surface can positively increase orthopedic implant durability.

Discovery of DS42450411 as a potent orally active hepcidin production inhibitor: Design and optimization of novel 4-aminopyrimidine derivatives.

Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis. The inhibition of hepcidin may be a favorable strategy for the treatment of anemia of chronic disease. Here, we have reported the design, synthesis, and structure-activity relationships (SAR) of a series of 4-aminopyrimidine compounds as inhibitors of hepcidin production. The optimization study of 1 led to the design of a potent and bioavailable inhibitor of hepcidin production, 34 (DS42450411), which showed serum hepcidin-lowering effects in a mouse model of interleukin-6-induced acute inflammation.

Synthesis and SAR studies of 3,6-disubstituted indazole derivatives as potent hepcidin production inhibitors.

Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. Inhibition of hepcidin could be a strategy favorable to treating anemia of chronic disease (ACD). We report herein the synthesis and structure-activity relationships (SARs) of a series of indazole compounds as hepcidin production inhibitors. The optimization study of compound 1 led to a potent hepcidin production inhibitor 45, which showed serum hepcidin lowering effects in a mouse IL-6 induced acute inflammatory model.

Discovery of DS79182026: A potent orally active hepcidin production inhibitor.

Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. Inhibition of hepcidin could be a strategy favorable to treating anemia of chronic disease (ACD). We report herein the synthesis and structure-activity relationships (SARs) of a series of benzisoxazole compounds as orally active hepcidin production inhibitors. The optimization study of multi kinase inhibitor 1 led to a potent and bioavailable hepcidin production inhibitor 38 (DS79182026), which showed serum hepcidin lowering effects in a mouse IL-6 induced acute inflammatory model.

Discovery of DS28120313 as a potent orally active hepcidin production inhibitor: Design and optimization of novel 4,6-disubstituted indazole derivatives.

Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis, and its inhibition could be a favorable strategy for treating anemia of chronic disease (ACD). Here, we report the design, synthesis and structure-activity relationships (SAR) of a series of 4,6-disubstituted indazole compounds as hepcidin production inhibitors. The optimization study of multi-kinase inhibitor 1 led to the design of a potent and bioavailable hepcidin production inhibitor, 32 (DS28120313), which showed serum hepcidin-lowering effects in an interleukin-6-induced acute inflammatory mouse model.

MitoTALEN: A General Approach to Reduce Mutant mtDNA Loads and Restore Oxidative Phosphorylation Function in Mitochondrial Diseases.

We have designed mitochondrially targeted transcription activator-like effector nucleases or mitoTALENs to cleave specific sequences in the mitochondrial DNA (mtDNA) with the goal of eliminating mtDNA carrying pathogenic point mutations. To test the generality of the approach, we designed mitoTALENs to target two relatively common pathogenic mtDNA point mutations associated with mitochondrial diseases: the m.8344A>G tRNA(Lys) gene mutation associated with myoclonic epilepsy with ragged red fibers (MERRF) and the m.13513G>A ND5 mutation associated with MELAS/Leigh syndrome. Transmitochondrial cybrid cells harbouring the respective heteroplasmic mtDNA mutations were transfected with the respective mitoTALEN and analyzed after different time periods. MitoTALENs efficiently reduced the levels of the targeted pathogenic mtDNAs in the respective cell lines. Functional assays showed that cells with heteroplasmic mutant mtDNA were able to recover respiratory capacity and oxidative phosphorylation enzymes activity after transfection with the mitoTALEN. To improve the design in the context of the low complexity of mtDNA, we designed shorter versions of the mitoTALEN specific for the MERRF m.8344A>G mutation. These shorter mitoTALENs also eliminated the mutant mtDNA. These reductions in size will improve our ability to package these large sequences into viral vectors, bringing the use of these genetic tools closer to clinical trials.

Adsorption characteristics of bovine serum albumin onto alumina with a specific crystalline structure.

Bone cement containing alumina particles with a specific crystalline structure exhibits the ability to bond with bone. These particles (AL-P) are mainly composed of delta-type alumina (δ-Al2O3). It is likely that some of the proteins present in the body environment are adsorbed onto the cement and influence the expression of its bioactivity. However, the effect that this adsorption of proteins has on the bone-bonding mechanism of bone cement has not yet been elucidated. In this study, we investigated the characteristics of the adsorption of bovine serum albumin (BSA) onto AL-P and compared them with those of its adsorption onto hydroxyapatite (HA), which also exhibits bone-bonding ability, as well as with those of adsorption onto alpha-type alumina (α-Al2O3), which does not bond with bone. The adsorption characteristics of BSA onto AL-P were very different from those onto α-Al2O3 but quite similar to those onto HA. It is speculated that BSA is adsorbed onto AL-P and HA by interionic interactions, while it is adsorbed onto α-Al2O3 by electrostatic attraction. The results suggest that the specific adsorption of albumin onto implant materials might play a role in the expression of the bone-bonding abilities of the materials.

Home blood pressure-lowering effect of a non-steroidal mineralocorticoid receptor blocker, esaxerenone, versus trichlormethiazide for uncontrolled hypertension: the EXCITE-HT randomized controlled study.

The EXCITE-HT study aimed to evaluate the efficacy and safety of esaxerenone versus thiazide diuretics (trichlormethiazide) as second-line treatment for Japanese patients with uncontrolled essential hypertension. This was a 12-week, multicenter, randomized, open-label, parallel-group study. The non-inferiority of esaxerenone to trichlormethiazide was confirmed if the upper limit of the two-sided 95% confidence interval (CI) for the difference in systolic blood pressure (SBP)/diastolic blood pressure (DBP) change between groups was below 3.9/2.1 mmHg. A total of 295 and 290 patients were included in the esaxerenone and trichlormethiazide groups, respectively. The non-inferiority of esaxerenone to trichlormethiazide was demonstrated: least squares mean change differences in morning home SBP/DBP at end of treatment (EOT) were -2.2 (95% CI, -3.6, -0.8) mmHg for SBP/-0.6 (-1.4, 0.2) mmHg for DBP. Morning home, bedtime home, and office BP significantly decreased (all p < 0.001) from baseline to EOT in both groups. The urinary albumin-to-creatinine ratio and N-terminal pro-brain natriuretic peptide level decreased from baseline to Week 12 in both groups, with no notable intergroup difference. Serum potassium elevations occurred more frequently with esaxerenone, while serum potassium reductions occurred more with trichlormethiazide. Uric acid elevations were observed in both groups, but more frequently with trichlormethiazide than esaxerenone. No cases of gout occurred in this study. Reductions in estimated glomerular filtration rate were similarly observed in both groups. EXCITE-HT is the first randomized controlled study to demonstrate evidence that esaxerenone is non-inferior to trichlormethiazide as second-line treatment for Japanese patients with uncontrolled essential hypertension, with no new safety concerns. The EXCITE-HT study demonstrated the non-inferiority of esaxerenone to trichlormethiazide in its morning home blood pressure lowering effect and safety profile in Japanese patients with uncontrolled essential hypertension who were previously treated with an angiotensin II receptor blocker or calcium channel blocker.

Efficacy of hydrated phospholipid polymer interfaces between all-polymer bearings for total hip arthroplasty.

Measurements of wear resistance and metal ion release are important for designing bearing couples or interfaces in total hip arthroplasty (THA). In this study, we investigated wear resistance and metal ion release of surface-modified metal-free all-polymer hip bearings, such as poly(ether-ether-ketone), (PEEK) on cross-linked polyethylene (PEEK-on-CLPE), with a hydrated gel-like surface layer, to propose an improved alternative to the conventional materials used to design THA bearings. The PEEK surface resulted in less metal ion release than the cobalt-chromium-molybdenum (Co-Cr-Mo) alloy surface owing to the lack of metal. The PEEK-on-CLPE bearing (6.33 mg/106 cycles) had lower wear (rate) than the bearing with Co-Cr-Mo alloy-on-CLPE (10.47 mg/106 cycles) under controlled laboratory conditions; the wear performance of the all-polymer hip bearings was further improved with hemi- or both-surface modified with a hydrated poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) layer (3.74 and 3.06 mg/106 cycles, respectively). The PMPC-grafted interface of PEEK-on-CLPE will be especially suitable for THA candidates. This study is of key importance for the design of lifelong THA and a better understanding of the limitations resulting from using PEEK. Further studies are necessary to evaluate the possibility of using this material in artificial hips.

Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetic Kidney Disease: A Multicenter, Open-Label, Prospective Study.

INTRODUCTION: Clinical data of esaxerenone in hypertensive patients with diabetic kidney disease (DKD) are lacking. We evaluated the efficacy and safety of esaxerenone in patients with DKD and an inadequate response to blood pressure (BP)-lowering treatment. METHODS: In this multicenter, open-label, prospective study, patients were divided into urinary albumin-to-creatinine ratio subcohorts (UACR < 30, 30 to < 300, and 300 to < 1000 mg/gCr). Esaxerenone was initiated at 1.25 mg/day and followed by incremental dose escalation based on BP and serum potassium level monitoring. The treatment period was 12 weeks. The primary endpoint was change in morning home systolic BP/diastolic BP (SBP/DBP) from baseline to end of treatment (EOT). Secondary endpoints included achievement rate of target BP, change in UACR from baseline, and safety. RESULTS: In total, 113 patients were enrolled. Morning home SBP/DBP significantly decreased from baseline to EOT in the total population (- 11.6/- 5.2 mmHg, both p < 0.001) and in all UACR subcohorts (all p < 0.001). The target BP achievement rate was 38.5%. Significant reductions in bedtime home and office BPs were also shown in the total population and all UACR subcohorts. UACR significantly improved from baseline to EOT in the total (- 50.9%, p < 0.001) and all UACR subcohorts (all p < 0.001). Incidence of serum potassium elevation as drug-related treatment emergent adverse events was 2.7%. The change from baseline in estimated glomerular filtration rate (eGFR) was - 4.8 mL/min/1.73 m2. CONCLUSION: Esaxerenone demonstrated a BP-lowering effect and improved albuminuria. The effects were consistent regardless of the severity of albuminuria without clinically relevant serum potassium elevation and eGFR reduction. CLINICAL TRIAL REGISTRATION: jRCTs06119002.

Selective blockade of P2Y12 receptors by prasugrel inhibits myocardial infarction induced by thrombotic coronary artery occlusion in rats.

We evaluated the effects of prasugrel, a third-generation thienopyridyl prodrug, on P2Y12 receptors, adenosine 5'-diphosphate (ADP)-induced platelet aggregation, and myocardial infarction (MI) in rats. Oral administration of prasugrel (0.3-3 mg/kg) resulted in the dose-related inhibition of washed platelet aggregation induced by ADP (1-10 µM). Ex vivo [H]-2-MeS-ADP binding to platelet P2Y12 receptors was also inhibited by prasugrel in a similar dose range. The antiaggregatory effects of prasugrel correlated strongly with P2Y12 blockade with correlation coefficients of 0.85-0.92, suggesting that the antiaggregatory activity of prasugrel largely reflected P2Y12 blockade achieved in vivo. We further examined the effects of the in vivo P2Y12 inhibition by prasugrel (1-10 mg/kg, po) on MI induced by thrombotic coronary artery occlusion in rats. In surviving rats, infarct size at 24 hours after photoirradiation was evaluated. In the vehicle group, necrosis area/total left ventricular area was 37.9% ± 6.8% (mean ± SE, n = 7). At all prasugrel doses tested (n = 7 for each dose), necrosis area/total left ventricular area was significantly smaller than that in the vehicle group: 14.4% ± 4.0% for 1 mg/kg (P < 0.01), 19.8% ± 4.5% for 3 mg/kg (P < 0.05), and 14.8% ± 3.6% for 10 mg/kg (P < 0.01). At the highest administered dose of prasugrel (10 mg/kg), blood pressure and heart rate were unchanged. Arrhythmia was observed in 5 of 7 animals in the vehicle group at 24 hours after irradiation; in contrast, no arrhythmia was found in the group treated with prasugrel (10 mg/kg). Taken together, these results demonstrate that prasugrel is a selective P2Y12 inhibitor in vivo, providing effective inhibition of platelet aggregation and MI in rats.

A nitrogen doped TiO2 layer on Ti metal for the enhanced formation of apatite.

Biomedical titanium metals subjected to gas under precisely regulated oxygen partial pressures (P(O2)) from 10(-18) to 10(5) Pa at 973 K for 1 h were soaked in a simulated body fluid (SBF), whose ion concentrations were nearly equal to those of human blood plasma, at 36.5°C for up to 7 days. The effect of oxygen partial pressures on apatite formation was assessed using X-ray diffraction (XRD), scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS) measurements. After heating, the weight of the oxide layer (mainly TiO(2)) formed on the titanium metal was found to increase with increased oxygen partial pressure. Nitrogen (N)-doped TiO(2) (Interstitial N) was formed under a P(O2) of 10(-14) Pa. At lower P(O2) (10(-18) Pa), only a titanium nitride layer (TiN and Ti(2)N) was formed. After soaking in SBF, apatite was detected on heat-treated titanium metal samples. The most apatite was formed, based on the growth rate calculated from the apatite coverage ratio, on the titanium metal heated under a P(O2) of 10(-14) Pa, followed by the sample heated under a P(O2) of 10 and 10(4) Pa (in N(2)). The titanium metal heated under a P(O2) of 10(5) Pa (in O(2)) experienced far less apatite formation than the former three titanium samples. Similarly, very little weight change was observed for the titanium metal heated under a P(O2) of 10(-18) Pa (in N(2)). During the experimental observation period (5 days, 36.5°C, SBF), the following relationship held: The growth rate of apatite decreased in the order P(O2) of 10(-14) Pa > P(O2) of 10 Pa ≥ P(O2) of 10(4) Pa > P(O2) of 10(5) Pa > > P(O2) of 10(-18) Pa. These results suggest that N-doped TiO(2) (Interstitial N) strongly induces apatite formation but samples coated only with titanium nitride do not. Thus, controlling the formation of N-doped TiO(2) is expected to improve the bioactivity of biomedical titanium metal.

Effects of a roughened femoral head and the locus of grafting on the wear resistance of the phospholipid polymer-grafted acetabular liner.

Although laboratory tests and mid-term clinical outcomes show the clinical safety and remarkable wear resistance of the highly cross-linked polyethylene (HXLPE) acetabular liner with a nanometer-scaled graft layer of poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), the wear resistance of the layer under severe abrasive conditions is concerning. We evaluated the effects of a roughened femoral head and the grafting locus on the wear resistance of the PMPC-grafted HXLPE liner and the effect of PMPC grafting on wear resistance of the HXLPE substrate by removing the PMPC-grafted layer using a severely roughened femoral head. Against a moderately roughened femoral head, the PMPC-grafted HXLPE liner showed negative wear, although an untreated HXLPE liner increased the wear by 154.1% compared with wear against a polished femoral head, confirming that PMPC grafts were unaffected. Against a severely roughened femoral head, the PMPC-grafted layer of the head contact area might be removed under severe conditions. However, the wear rate was reduced by 52.5% compared to that of untreated HXLPE liners. Moreover, the head non-contact area-modified PMPC-grafted HXLPE liner against a polished femoral head reduced the wear by 76.8% compared with untreated HXLPE liner; thus, this area may be also important in the development of fluid-film lubrication. STATEMENT OF SIGNIFICANCE: Here we describe effects of a roughened femoral head and the locus of grafting on the wear-resistance of the phospholipid polymer grafted highly cross-linked polyethylene (PMPC-HXLPE) liner. Against a moderately roughened femoral head, the PMPC-HXLPE liner showed negative wear, confirming that PMPC grafts were unaffected. After removing the PMPC layer of the head contact area using a severely roughened femoral head, the wear rate not only exceeded that of untreated HXLPE liners, but was reduced by 52.5%, confirming that PMPC grafting does not affect the wear-resistance of the HXLPE substrate. In addition, the head non-contact area-modified PMPC-HXLPE liner reduced the wear by 76.8%. Thus, this area may also may be important in the development of fluid-film lubrication.

Repeat oral dosing of prasugrel, a novel P2Y12 receptor inhibitor, results in cumulative and potent antiplatelet and antithrombotic activity in several animal species.

Antiplatelet and antithrombotic activity of multiple oral dosing of prasugrel were evaluated in several animal species. Prasugrel's active metabolite concentration-relatedly inhibited in vitro ADP-induced aggregation of rat, rabbit, dog, monkey and human platelets. Oral administration of prasugrel to dogs (0.03-0.3 mg/kg/day) and monkeys (0.1 and 0.3 mg/kg/day) once a day for 14 days resulted in potent, dose-related and cumulative inhibition of ADP-induced platelet aggregation. The inhibitory effects reached a plateau on days 3 to 5 and thereafter were maintained during dosing. Inhibition decreased gradually after cessation of dosing with near full recovery by 7 days after last dose. Antiplatelet and antithrombotic activity of prasugrel and clopidogrel were further examined in rats. Multiple oral dosing of prasugrel (0.3-3 mg/kg/day) to rats resulted in more potent inhibition of platelet aggregation compared to clopidogrel (3-30 mg/kg/day) and ticlopidine (30-300 mg/kg/day). Separate experiments confirmed that platelet inhibition was associated with inhibition of [(3)H]-2-methylthio-ADP binding to rat platelets. In a rat model of electrically-induced arterial thrombosis, prasugrel (0.1-1 mg/kg/day, p.o.) significantly prolonged the time to arterial occlusion and increased the duration of arterial patency. The inhibition of platelet aggregation of prasugrel was about 10 and 300 times more potent than clopidogrel and ticlopidine, respectively. Overall these results show that in several species multiple oral administration of prasugrel results in more potent inhibition of platelet aggregation and thrombus formation than clopidogrel and ticlopidine, and that these effects are mediated by inhibition of platelet ADP receptors.

A phospholipid polymer graft layer affords high resistance for wear and oxidation under load bearing conditions.

Manipulating the surface and substrate of cross-linked polyethylene (CLPE) is an essential approach for obtaining life-long orthopedic bearings. We therefore proposed a bearing material comprised of an antioxidative substrate generated by vitamin E blending (HD-CLPE[VE]) with a poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)-grafted surface, and investigated its wear resistance and oxidative stability under accelerated aging and load bearing conditions. Neither the hydration nor friction kinetics of the molecular network structure of the PMPC-grafted surface or the HD-CLPE(VE) substrate were influenced by accelerated aging but rather exhibited high stability even under high oxidation conditions. The characteristics of the PMPC-grafted surface improved the wear and impact fatigue resistance of the HD-CLPE(VE) liner regardless of accelerated aging. Notably, the PMPC-grafted surface was found to affect the potential oxidative stability at the rim part of the acetabular liner. PMPC chains serve several important functions on the surface regardless of load bearing, such as high lubricity or low lipophilicity attributed to phosphorylcholine groups and/or surrounding water-fluid film, and suppression of lipid diffusion attributed to methacrylate main chains on the surface. Together, these results provide preliminary evidence that the PMPC graft layer and vitamin E-blended substrate might positively affect the extent of orthopedic implant durability.

Wear resistance of poly(2-methacryloyloxyethyl phosphorylcholine)-grafted carbon fiber reinforced poly(ether ether ketone) liners against metal and ceramic femoral heads.

Younger, active patients who undergo total hip arthroplasty (THA) have increasing needs for wider range of motion and improved stability of the joint. Therefore, bearing materials having not only higher wear resistance but also mechanical strength are required. Carbon fiber-reinforced poly(ether ether ketone) (CFR-PEEK) is known as a super engineering plastic that has great mechanical strength. In this study, we focused on poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)-grafted CFR-PEEK and investigated the effects of PMPC grafting and the femoral heads materials on the wear properties of CFR-PEEK liners. Compared with untreated CFR-PEEK, the PMPC-grafted CFR-PEEK surface revealed higher wettability and lower friction properties under aqueous circumstances. In the hip simulator wear test, wear particles generated from the PMPC-grafted CFR-PEEK liners were fewer than those of the untreated CFR-PEEK liners. There were no significant differences in the size and the morphology of the wear particles between the differences of PMPC-grafting and the counter femoral heads. Zirconia-toughened alumina (ZTA) femoral heads had significantly smoother surfaces compared to cobalt-chromium-molybdenum alloy femoral heads after the hip simulator test. Thus, we conclude that the bearing combination of the PMPC-grafted CFR-PEEK liner and ZTA head is expected to be a lifelong bearing interface in THA. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1028-1037, 2018.

The influence of P2Y12 receptor deficiency on the platelet inhibitory activities of prasugrel in a mouse model: evidence for specific inhibition of P2Y12 receptors by prasugrel.

Prasugrel is a novel orally active thienopyridine with faster, higher and more reliable inhibition of platelet aggregation than clopidogrel reflecting its metabolism in vivo to an active metabolite with selective P2Y(12) antagonistic activity. Several lines of evidence support the contention that prasugrel provides selective P2Y(12) receptor antagonistic activity. To date, however, direct evidence of P2Y(12) specific action by prasugrel in vivo is limited. In the present study, effects of prasugrel on ex vivo platelet aggregation were examined in wild type (WT) and P2Y(12)(-/-) mice. In WT mice, prasugrel showed platelet inhibition that was 8.2 times more potent than clopidogrel. In P2Y(12)(-/-) mice, ADP induced platelet aggregation was minimal, and its extent was similar to that in prasugrel-treated WT mice. In addition, no further inhibition of platelet aggregation was observed after administration of prasugrel to P2Y(12)(-/-) mice. Furthermore, prasugrel-treated WT mice showed similar aggregation patterns using collagen- and murine PAR-4 agonist peptide to those of P2Y(12)(-/-) mice treated with vehicle or prasugrel. Overall, these results clearly provide additional in vivo evidence that prasugrel has selective P2Y(12) antagonistic activity.

Enantioselective incorporation of dicarboxylate guests by octacalcium phosphate.

Enantioselectivity by octacalcium phosphate (OCP) is revealed through the incorporation of (S)-(-)-methylsuccinic acid (MeSuc) into its crystal lattice, with hardly any (R)-(+)-MeSuc incorporated. This phenomenon clearly indicates that OCP recognizes the steric structures of guest molecules, extending chiral recognition in inorganic materials to three-dimensional crystal growth.