Discovery of 5-aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones as positive allosteric modulators of metabotropic glutamate subtype-2 (mGlu2) receptors with efficacy in a preclinical model of psychosis.

Optimization of a benzimidazolone template for potency and physical properties revealed 5-aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones as a key template on which to develop a new series of mGlu2 positive allosteric modulators (PAMs). Systematic investigation of aryl-SAR led to the identification of compound 27 as a potent and highly selective mGlu2 PAM with sufficient pharmacokinetics to advance to preclinical models of psychosis. Gratifyingly, compound 27 showed full efficacy in the PCP- and MK-801-induced hyperlocomotion assay in rats at CSF concentrations consistent with mGlu2 PAM potency.

Enhanced Photogating Gain in Scalable MoS2 Plasmonic Photodetectors via Resonant Plasmonic Metasurfaces.

Absorption of photons in atomically thin materials has become a challenge in the realization of ultrathin, high-performance optoelectronics. While numerous schemes have been used to enhance absorption in 2D semiconductors, such enhanced device performance in scalable monolayer photodetectors remains unattained. Here, we demonstrate wafer-scale integration of monolayer single-crystal MoS2 photodetectors with a nitride-based resonant plasmonic metasurface to achieve a high detectivity of 2.58 × 1012 Jones with a record-low dark current of 8 pA and long-term stability over 40 days. Upon comparison with control devices, we observe an overall enhancement factor of >100; this can be attributed to the local strong EM field enhanced photogating effect by the resonant plasmonic metasurface. Considering the compatibility of 2D semiconductors and hafnium nitride with the Si CMOS process and their scalability across wafer sizes, our results facilitate the smooth incorporation of 2D semiconductor-based photodetectors into the fields of imaging, sensing, and optical communication applications.

Fluorinated Isoindolinone-Based Glucosylceramide Synthase Inhibitors with Low Human Dose Projections.

Inhibition of glucosylceramide synthase (GCS) has been proposed as a therapeutic strategy for the treatment of Parkinson's Disease (PD), particularly in patients where glycosphingolipid accumulation and lysosomal impairment are thought to be contributing to disease progression. Herein, we report the late-stage optimization of an orally bioavailable and CNS penetrant isoindolinone class of GCS inhibitors. Starting from advanced lead 1, we describe efforts to identify an improved compound with a lower human dose projection, minimal P-glycoprotein (P-gp) efflux, and acceptable pregnane X receptor (PXR) profile through fluorine substitution. Our strategy involved the use of predicted volume ligand efficiency to advance compounds with greater potential for low human doses down our screening funnel. We also applied minimized electrostatic potentials (Vmin) calculations for hydrogen bond acceptor sites to rationalize P-gp SAR. Together, our strategies enabled the alignment of a lower human dose with reduced P-gp efflux, and favorable PXR selectivity for the discovery of compound 12.

In vitro assessment of drug-drug interaction potential of boceprevir associated with drug metabolizing enzymes and transporters.

The inhibitory effect of boceprevir (BOC), an inhibitor of hepatitis C virus nonstructural protein 3 protease was evaluated in vitro against a panel of drug-metabolizing enzymes and transporters. BOC, a known substrate for cytochrome P450 (P450) CYP3A and aldo-ketoreductases, was a reversible time-dependent inhibitor (k(inact) = 0.12 minute(-1), K(I) = 6.1 µM) of CYP3A4/5 but not an inhibitor of other major P450s, nor of UDP-glucuronosyltransferases 1A1 and 2B7. BOC showed weak to no inhibition of breast cancer resistance protein (BCRP), P-glycoprotein (Pgp), or multidrug resistance protein 2. It was a moderate inhibitor of organic anion transporting polypeptide (OATP) 1B1 and 1B3, with an IC(50) of 18 and 4.9 µM, respectively. In human hepatocytes, BOC inhibited CYP3A-mediated metabolism of midazolam, OATP1B-mediated hepatic uptake of pitavastatin, and both the uptake and metabolism of atorvastatin. The inhibitory potency of BOC was lower than known inhibitors of CYP3A (ketoconazole), OATP1B (rifampin), or both (telaprevir). BOC was a substrate for Pgp and BCRP but not for OATP1B1, OATP1B3, OATP2B1, organic cation transporter, or sodium/taurocholate cotransporting peptide. Overall, our data suggest that BOC has the potential to cause pharmacokinetic interactions via inhibition of CYP3A and CYP3A/OATP1B interplay, with the interaction magnitude lower than those observed with known potent inhibitors. Conversely, pharmacokinetic interactions of BOC, either as a perpetrator or victim, via other major P450s and transporters tested are less likely to be of clinical significance. The results from clinical drug-drug interaction studies conducted thus far are generally supportive of these conclusions.

Developing a mechanistic understanding of the nonlinear pharmacokinetics of letermovir and prospective drug interaction with everolimus using physiological-based pharmacokinetic modeling.

Letermovir is approved for use in cytomegalovirus-seropositive hematopoietic stem cell transplant recipients and is investigated in other transplant settings. Nonlinear pharmacokinetics (PKs) were observed in clinical studies after intravenous and oral dosing across a wide dose range, including the efficacious doses of 240 and 480 mg. A physiologically-based PK (PBPK) model for letermovir was built to develop a plausible explanation for the nonlinear PKs observed in clinical studies. In vitro studies suggested that letermovir elimination and distribution are mediated by saturable uridine glucuronosyltransferases (UGT)-metabolism and by saturable hepatic uptake via organic anion-transporting polypeptides (OATP) 1B. A sensitivity analysis of parameters describing the metabolism and distribution mechanisms indicated that the greater than dose-proportional increase in letermovir exposure is best described by a saturable OATP1B-mediated transport. This PBPK model was further used to evaluate the drug interaction potential between letermovir and everolimus, an immunosuppressant that may be co-administered with letermovir depending on regions. Because letermovir inhibits cytochrome P450 (CYP) 3A and everolimus is a known CYP3A substrate, an interaction when concomitantly administered is anticipated. The drug-drug interaction simulation confirmed that letermovir will likely increase everolimus are under the curve by 2.5-fold, consistent with the moderate increase in exposure observed with midazolam in the clinic. The output highlights the importance of drug monitoring, which is common clinical practice for everolimus to maintain safe and efficacious drug concentrations in the targeted patient population when concomitantly administered with letermovir.

Pyrazole Ureas as Low Dose, CNS Penetrant Glucosylceramide Synthase Inhibitors for the Treatment of Parkinson's Disease.

Parkinson's disease is the second most prevalent progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Loss-of-function mutations in GBA, the gene that encodes for the lysosomal enzyme glucosylcerebrosidase, are a major genetic risk factor for the development of Parkinson's disease potentially through the accumulation of glucosylceramide and glucosylsphingosine in the CNS. A therapeutic strategy to reduce glycosphingolipid accumulation in the CNS would entail inhibition of the enzyme responsible for their synthesis, glucosylceramide synthase (GCS). Herein, we report the optimization of a bicyclic pyrazole amide GCS inhibitor discovered through HTS to low dose, oral, CNS penetrant, bicyclic pyrazole urea GCSi's with in vivo activity in mouse models and ex vivo activity in iPSC neuronal models of synucleinopathy and lysosomal dysfunction. This was accomplished through the judicious use of parallel medicinal chemistry, direct-to-biology screening, physics-based rationalization of transporter profiles, pharmacophore modeling, and use a novel metric: volume ligand efficiency.

Pyridyl amides as potent inhibitors of T-type calcium channels.

A novel series of amide T-type calcium channel antagonists were prepared and evaluated using in vitro and in vivo assays. Optimization of the screening hit 3 led to identification of the potent and selective T-type antagonist 37 that displayed in vivo efficacy in rodent models of epilepsy and sleep.

Physiologically Based Pharmacokinetic Modeling of Doravirine and Its Major Metabolite to Support Dose Adjustment With Rifabutin.

Doravirine, a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus 1 (HIV-1), is predominantly cleared by cytochrome P450 (CYP) 3A4 and metabolized to an oxidative metabolite (M9). Coadministration with rifabutin, a moderate CYP3A4 inducer, decreased doravirine exposure. Based on nonparametric superposition modeling, a doravirine dose adjustment from 100 mg once daily to 100 mg twice daily during rifabutin coadministration was proposed. However, M9 exposure may also be impacted by induction, in addition to the dose adjustment. As M9 concentrations have not been quantified in previous clinical studies, a physiologically based pharmacokinetic model was developed to investigate the change in M9 exposure when doravirine is coadministered with CYP3A inducers. Simulations demonstrated that although CYP3A induction increases doravirine clearance by up to 4.4-fold, M9 exposure is increased by only 1.2-fold relative to exposures for doravirine 100 mg once daily in the absence of CYP3A induction. Thus, a 2.4-fold increase in M9 exposure relative to the clinical dose of doravirine is anticipated when doravirine 100 mg twice daily is coadministered with rifabutin. In a subsequent clinical trial, doravirine and M9 exposures, when doravirine 100 mg twice daily was coadministered with rifabutin, were found to be consistent with model predictions using rifampin and efavirenz as representative inducers. These findings support the dose adjustment to doravirine 100 mg twice daily when coadministered with rifabutin.

Effects of aerobic walking on cognitive function in patients with schizophrenia: A randomized controlled trial.

Cognitive deficits, which are core manifestations in schizophrenia and exhibit a limited response to antipsychotic treatment, contribute to poor treatment outcomes and functional disability. Evidence on the effect of aerobic walking (AW) and exercise intensity on cognitive function in patients with schizophrenia is lacking. In total, 79 patients with schizophrenia were recruited for a 12-week randomized control trial and allocated to the treatment-as-usual (TAU, n = 38) and treatment-as-usual plus AW (TAW, n = 39) groups. The TAW participants joined a supervised 12-week AW program consisting of 30-min sessions five times per week while wearing a Fitbit Charge 2 device. Cognitive function was evaluated using the Brief Assessment of Cognition in Schizophrenia. After randomization, 67 (34 TAU and 33 TAW) participants joined the 12-week trial and were included in the intention-to-treat analysis. Multivariate general linear model repeated measures analysis revealed no significant time × group interaction effect on cognitive function changes between the TAU and TAW groups and a marginally significant group effect on verbal fluency (p = 0.09). The interaction effect of time and treatment group on verbal fluency (p = 0.05) was marginally significant between the high and low AW intensity groups, whereas a significant group effect on attention and processing speed (p = 0.04) was observed. Supervised 12-week AW of moderate intensity may have potential cognitive benefits for patients with schizophrenia.

Discovery and expanded SAR of 4,4-disubstituted quinazolin-2-ones as potent T-type calcium channel antagonists.

The discovery and synthesis of 4,4-disubstituted quinazolinones as T-type calcium channel antagonists is reported. Based on lead compounds 2 and 3, a focused SAR campaign driven by the optimization of potency, metabolic stability, and pharmacokinetic profile identified 45 as a potent T-type Ca(2+) channel antagonist with minimized PXR activation. In vivo, 45 suppressed seizure frequency in a rat model of absence epilepsy and showed significant alterations of sleep architecture after oral dosing to rats as measured by EEG.

3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones as positive allosteric modulators of mGluR2 for the treatment of schizophrenia: Hit-to-lead efforts.

Hit to lead optimization of (5R)-5-hexyl-3-phenyl-1,3-oxazolidin-2-one as a positive allosteric modulator of mGluR2 is described. Improvements in potency and metabolic stability were achieved through SAR on both ends of the oxazolidinone. An optimized lead compound was found to be brain penetrant and active in a rat ketamine-induced hyperlocomotion model for antipsychotic activity.

CYP2C75-involved autoinduction of metabolism in rhesus monkeys of methyl 3-chloro-3'-fluoro-4'-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]ethyl}-1,1'-biphenyl-2-carboxylate (MK-0686), a bradykinin B1 receptor antagonist.

After oral treatment (once daily) for 4 weeks with the potent bradykinin B(1) receptor antagonist methyl 3-chloro-3'-fluoro-4'-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)-amino]ethyl}-1,1'-biphenyl-2-carboxylate (MK-0686), rhesus monkeys (Macaca mulatta) exhibited significantly reduced systemic exposure of the compound in a dose-dependent manner, suggesting an occurrence of autoinduction of MK-0686 metabolism. This possibility is supported by two observations. 1) MK-0686 was primarily eliminated via biotransformation in rhesus monkeys, with oxidation on the chlorophenyl ring as one of the major metabolic pathways. This reaction led to appreciable formation of a dihydrodiol (M11) and a hydroxyl (M13) product in rhesus liver microsomes supplemented with NADPH. 2) The formation rate of these two metabolites determined in liver microsomes from MK-0686-treated groups was > or = 2-fold greater than the value for a control group. Studies with recombinant rhesus P450s and monoclonal antibodies against human P450 enzymes suggested that CYP2C75 played an important role in the formation of M11 and M13. The induction of this enzyme by MK-0686 was further confirmed by a concentration-dependent increase of its mRNA in rhesus hepatocytes, and, more convincingly, the enhanced CYP2C proteins and catalytic activities toward CYP2C75 probe substrates in liver microsomes from MK-0686-treated animals. Furthermore, a good correlation was observed between the rates of M11 and M13 formation and hydroxylase activities toward probe substrates determined in a panel of liver microsomal preparations from control and MK-0686-treated animals. Therefore, MK-0686, both a substrate and inducer for CYP2C75, caused autoinduction of its own metabolism in rhesus monkeys by increasing the expression of this enzyme.

Diclofenac hydroxylation in monkeys: efficiency, regioselectivity, and response to inhibitors.

The catalytic efficiency, regioselectivity, and response to chemical inhibitors of diclofenac (DF) hydroxylation in three Old World monkey liver microsomes (rhesus, cynomolgus, and African green monkey) are different from those determined with human liver microsomes. In contrast to the high affinity-high capacity (low Km-high Vmax) characteristics of DF 4'-hydroxylation in humans, this reaction proceeded in all monkey species with catalytic efficiencies >20-fold lower. However, DF 5-hydroxylation, a negligible reaction in human liver microsomes, was kinetically favored in monkeys mainly due to the increased Vmax values. Chemical inhibitors (reversible or mechanism-based) selective to human CYP3A4 and CYP2C9 failed to differentiate monkey orthologs involved in DF hydroxylation. Immunoinhibition studies with monoclonal antibodies against human CYPs revealed the major contribution of CYP2C and CYP3A to 4'- and to 5-hydroxylation, respectively, in rhesus and cynomolgus liver microsomes. However, in African green monkeys, in addition to CYP2C, CYP3A also appeared to be involved in 4'-hydroxylation. Further studies with recombinant rhesus and African green monkey CYP2C and CYP3A enzymes (rhesus CYP2C75, 2C74, and 3A64; African green monkey CYP2C9agm and CYP3A4agm) confirmed the major role of CYP enzymes of these two subfamilies in DF 4'- and 5-hydroxylation. Clearly, while monkey CYP2C and 3A enzymes retain the same substrate selectivity towards DF hydroxylation as their human orthologs, their altered catalytic efficiency and response to chemical inhibitors may indicate different structural features of active sites as opposed to human orthologs.

Prediction of Metabolic Clearance for Low-Turnover Compounds Using Plated Hepatocytes with Enzyme Activity Correction.

BACKGROUND AND OBJECTIVES: Prediction of metabolic clearance has been a challenge for compounds exhibiting minimal turnover in typical in vitro stability experiments. The aim of the current study is to evaluate the utilization of plated human hepatocytes to predict intrinsic clearance of low-turnover compounds. METHODS: The disappearance of test compounds was determined for up to 48 h while enzyme activities in plated hepatocytes were monitored concurrently in a complimentary experiment. RESULTS: Consistent with literature reports, marked time-dependent loss of cytochrome P450 (CYP) enzyme activities was observed during the 48-h incubation period. To account for the loss of enzyme activities, a term "fraction of activity remaining" was calculated based on area-under-the-curve derived from the average rate of activity loss (k avg), and then applied as a correction factor for intrinsic clearance determination. Twelve compounds were selected in this study to cover phase I and phase II biotransformation pathways, with in vivo intrinsic clearance values, representing metabolic clearance only, ranging from 0.66 to 47 ml/min/kg. Determination of in vitro intrinsic clearance using three individual preparations of hepatocytes revealed a reasonably good agreement (generally within threefold) between the predicted and the observed metabolic clearance for all 12 compounds tested. CONCLUSIONS: The current results indicated that plated hepatocytes can be utilized to provide clearance predictions for compounds with low-turnover in humans when corrected for the loss in enzyme activities.

Influences of Aerobic Dance on Cognitive Performance in Adults with Schizophrenia.

Cognitive impairment is one of the core features of schizophrenia. This study examined the influences of an aerobic dance programme on the cognitive functions of people with schizophrenia. A quasi-experimental matched-control design was applied. The experimental group (n = 17) participated in a 60-minute aerobic dance group class three times a week for 3 months. The control group (n = 19) participated in colouring and handwriting activities. Cognitive functions were measured before and after the interventions for both groups. The intervention group experienced significant improvements in processing speed, memory and executive function, whereas no significant changes were noted in any measures in the control group. While there were no significant between-group differences, the data showed approximately medium effect sizes that favoured the intervention group in regard to processing speed (Cohen's d = 0.51), memory (d = 0.35-0.41) and the spontaneity and fluency aspects of executive function (d = 0.51). While the small sample size and lack of randomization were the primary methodological shortcomings, this study provides preliminary results supporting aerobic dance as an adjunct activity-based intervention to improve cognitive functions in people with schizophrenia. More rigorous studies are needed to validate the findings. Copyright © 2016 John Wiley & Sons, Ltd.

Optimization of Novel Aza-benzimidazolone mGluR2 PAMs with Respect to LLE and PK Properties and Mitigation of CYP TDI.

Investigation of a novel amino-aza-benzimidazolone structural class of positive allosteric modulators (PAMs) of metabotropic glutamate receptor 2 (mGluR2) identified [2.2.2]-bicyclic amine 12 as an intriguing lead structure due to its promising physicochemical properties and lipophilic ligand efficiency (LLE). Further optimization led to chiral amide 18, which exhibited strong in vitro activity and attractive pharmacokinetic (PK) properties. Hypothesis-driven target design identified compound 21 as a potent, highly selective, orally bioavailable mGluR2 PAM, which addressed a CYP time-dependent inhibition (TDI) liability of 18, while maintaining excellent drug-like properties with robust in vivo activity in a clinically validated model of antipsychotic potential.

Discovery of Oxazolobenzimidazoles as Positive Allosteric Modulators for the mGluR2 Receptor.

Novel oxazolobenzimidazoles are described as potent and selective positive allosteric modulators of the metabotropic glutamate receptor 2. The discovery of this class and optimization of its physical and pharmacokinetic properties led to the identification of potent and orally bioavailable compounds (20 and 21) as advanced leads. Compound 20 (TBPCOB) was shown to have robust activity in a PCP-induced hyperlocomotion model in rat, an assay responsive to clinical antipsychotic treatments for schizophrenia.

Discovery of 4,4-Disubstituted Quinazolin-2-ones as T-Type Calcium Channel Antagonists.

A novel series of quinazolinone T-type calcium channel antagonists have been prepared and evaluated using in vitro and in vivo assays. Optimization of the screening hit 3 by modifications of the 3- and 4-positions of the quinazolinone ring afforded potent and selective antagonists that displayed in vivo central nervous system efficacy in epilepsy and tremor models, as well as significant effects on rat active wake as measured by electrocorticogram.

Short-acting T-type calcium channel antagonists significantly modify sleep architecture in rodents.

A novel phenyl acetamide series of short-acting T-type calcium channel antagonists has been identified and evaluated using in vitro and in vivo assays. Heterocycle substitutions of the 4-position of the phenyl acetamides afforded potent and selective antagonists that exhibited desired short plasma half-lives across preclinical species. Lead compound TTA-A8 emerged as a compound with excellent in vivo efficacy as indicated by its significant modulation of rat sleep architecture in an EEG telemetry model, favorable pharmacokinetic properties, and excellent preclinical safety. TTA-A8 recently progressed into human clinical trials, and in line with our predictions, preliminary studies (n = 12) with a 20 mg oral dose afforded a high C max of 1.82 ± 0.274 µM with an apparent terminal half-life of 3.0 ± 1.1 h.

Effect of P-glycoprotein-mediated efflux on cerebrospinal fluid concentrations in rhesus monkeys.

Brain penetration of drugs which are subject to P-glycoprotein (Pgp)-mediated efflux is attenuated, as manifested by the fact that the cerebrospinal fluid concentration (C(CSF)), a good surrogate of the unbound brain concentration (C(ub)), is lower than the unbound plasma concentration (C(up)) for Pgp substrates. In rodents, the attenuation magnitude of brain penetration by Pgp-mediated efflux has been estimated by correlating the ratio of CSF to plasma exposures (C(CSF)/C(p)) with the unbound fraction in plasma (f(u)) upon the incorporation of the in vivo or in vitro Pgp-mediated efflux ratios (ERs). In the present work, we investigated the impact of Pgp-mediated efflux on C(CSF) in monkeys. Following intravenous administration to cisterna magna ported rhesus monkeys, the CSF and plasma concentrations were determined for 25 compounds from three discovery programs. We also evaluated their f(u) in rhesus plasma and ER in human and African green monkey MDR-transfected LLC-PK1 cells. These compounds varied significantly in the f(u) (0.025-0.73), and 24 out of 25 are considered Pgp substrates based on their appreciable directional transport (ER>2). The C(CSF)/C(p) was significantly lower than the corresponding f(u) (>or=3-fold) for 16 compounds regardless of a significant correlation (R(2)=0.59, p=4 x 10(-5)) when the C(CSF)/C(p) was plotted against the f(u). When the f(u) was normalized to the ER (f(u)/ER) the correlation was improved (R(2)=0.75, p=8 x 10(-8)). More importantly, only one compound showed the C(CSF)/C(p) that exceeded 3-fold of the normalized f(u). The results suggest that the impact of Pgp-mediated efflux in monkeys, similar to the case in rodents, is reasonably reflected by the gradient between the free concentrations in plasma and in CSF. Therefore, f(u) and Pgp ER may serve as useful measurements in estimating in vivo C(CSF)/C(p) ratios in monkeys, and potentially in humans.