Provider and Practice Characteristics and Perceived Barriers Associated With Different Levels of Adolescent SBIRT Implementation Among a National Sample of US Pediatricians.

Pediatrician Screening, Brief Intervention, and Referral to Treatment (SBIRT) practices vary widely, though little is known about the correlates of SBIRT implementation. Using data from a national sample of US pediatricians who treat adolescents (n = 250), we characterized self-reported utilization rates of SBIRT among US pediatricians and identified provider- and practice-level characteristics and barriers associated with SBIRT utilization. All participants completed an electronic survey querying the demographics, practice patterns, and perceived barriers related to SBIRT practices. Our results showed that 88% of respondents reported screening for substance use annually, but only 26% used structured/validated screening instruments. Furthermore, 40% of respondents provided evidence-based brief interventions, and only 11% implemented all core SBIRT practices. Common barriers (eg, confidentiality and insufficient time) and unique provider- and setting-specific barriers to implementation were identified. These findings indicate that although most pediatricians deliver some SBIRT components in their practice, few implement the full SBIRT model, and barriers persist.

Do the Transmissible Liability Index (TLI) and Adolescent Cannabis Use Predict Paranoid and Schizotypal Symptoms at Young Adulthood?

Background: Adolescent cannabis use is an established risk factor for the development of psychosis, but the premorbid vulnerability factors and specificity versus generality of the psychotic symptom domains affected in cannabis-psychosis relationships remain incompletely understood. To improve our understanding of these relationships, we used longitudinal data to examine the individual and interactive effects of preadolescent transmissible liability to substance use disorders (SUD), measured via the transmissible liability index (TLI), and adolescent cannabis use on the development of two distinct psychotic symptom domains, paranoid and schizotypal personality traits in young adulthood. Methods: We performed secondary analysis of data from the Center for Education and Drug Abuse (CEDAR) study, which longitudinally assessed offspring of men with (N = 211) and without (N = 237) lifetime history of SUD at ages 10-12, and across adolescence as they transitioned to young adulthood. TLI scores were calculated at age 10-12, self-reported cannabis use was assessed at age 16, and paranoid and schizotypal symptoms were assessed at age 19. Results: Cannabis use at age 16 and family history of SUD were significantly associated with paranoid and schizotypal symptoms at age 19, but TLI scores were not. The interactive effect of TLI x cannabis use was also not significant. Paranoid and schizotypal symptoms showed different dose-dependent sensitivities to cannabis exposure at age 16. Conclusions: These findings indicate that adolescent cannabis use and family history of SUD differentially contribute to the development of paranoid and schizotypal personality traits through mechanisms that do not include behavioral disinhibition.

An interaction between early threat exposure and the oxytocin receptor in females: Disorder-specific versus general risk for psychopathology and social-emotional mediators.

Early threat exposure is a transdiagnostic risk factor for psychopathology, and evidence suggests that genetic variation in the oxytocin receptor (OXTR) moderates this association. However, it is unclear if this gene-by-environment (G×E) interaction is tied to unique risk for disorder-specific outcomes or instead increases shared risk for general psychopathology. Moreover, little is known about how this G×E interaction increases risk. The current study utilized a prospective, longitudinal sample of females (n = 2,020) to examine: (a) whether the interaction between early threat exposure and OXTR variation (rs53576, rs2254298) confers risk for disorder-specific outcomes (depression, anxiety, borderline and antisocial personality disorders) and/or general psychopathology in early adulthood; and (b) whether social-emotional deficits (emotion dysregulation, callousness, attachment quality) during adolescence constitute mediating mechanisms. Consistent with hypotheses, the interactive effects of early threat exposure and OXTR variation (rs53576) predicted general psychopathology, with threat-exposed women carrying at least one copy of the rs53576 A-allele at greatest risk. This interaction was mediated via emotional dysregulation in adolescence, with threat-exposed A-allele carriers demonstrating greater emotion dysregulation, and greater emotion dysregulation predicting general psychopathology in early adulthood. Findings suggest that this G×E places women at risk for a broad range of psychopathology via effects on emotion dysregulation.

Editorial: Parenting in Mind: Neurodevelopment and the Influence of Children's Most Profound Relationship.

Parenting style, defined as the context of parenting practice,1 is foundational to research on mother-child relationships because it is observable, amenable to intervention, and influences risk of mental illness in offspring. For example, a recent systematic review demonstrates an association between negative parenting styles and the development of internalizing disorders in children.2 Therapies incorporating parenting style are standard treatment for youth with externalizing disorders. Given that the mother-child relationship is ever-present starting before birth and influences mental health, there is keen interest to elucidate the influence of parenting style on children's neurobiological development.

Discovery of TRPM8 Antagonist ( S)-6-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinic Acid (AMG 333), a Clinical Candidate for the Treatment of Migraine.

Transient-receptor-potential melastatin 8 (TRPM8), the predominant mammalian cold-temperature thermosensor, is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system, including nerve circuitry implicated in migraine pathogenesis: the trigeminal and pterygopalatine ganglia. Genomewide association studies have identified an association between TRPM8 and reduced risk of migraine. This disclosure focuses on medicinal-chemistry efforts to improve the druglike properties of initial leads, particularly removal of CYP3A4-induction liability and improvement of pharmacokinetic properties. A novel series of biarylmethanamide TRPM8 antagonists was developed, and a subset of leads were evaluated in preclinical toxicology studies to identify a clinical candidate with an acceptable preclinical safety profile leading to clinical candidate AMG 333, a potent and highly selective antagonist of TRPM8 that was evaluated in human clinical trials.

Parsing Heterogeneity in the Brain Connectivity of Depressed and Healthy Adults During Positive Mood.

BACKGROUND: There is well-known heterogeneity in affective mechanisms in depression that may extend to positive affect. We used data-driven parsing of neural connectivity to reveal subgroups present across depressed and healthy individuals during positive processing, informing targets for mechanistic intervention. METHODS: Ninety-two individuals (68 depressed patients, 24 never-depressed control subjects) completed a sustained positive mood induction during functional magnetic resonance imaging. Directed functional connectivity paths within a depression-relevant network were characterized using Group Iterative Multiple Model Estimation (GIMME), a method shown to accurately recover the direction and presence of connectivity paths in individual participants. During model selection, individuals were clustered using community detection on neural connectivity estimates. Subgroups were externally tested across multiple levels of analysis. RESULTS: Two connectivity-based subgroups emerged: subgroup A, characterized by weaker connectivity overall, and subgroup B, exhibiting hyperconnectivity (relative to subgroup A), particularly among ventral affective regions. Subgroup predicted diagnostic status (subgroup B contained 81% of patients; 50% of control subjects; χ2 = 8.6, p = .003) and default mode network connectivity during a separate resting-state task. Among patients, subgroup B members had higher self-reported symptoms, lower sustained positive mood during the induction, and higher negative bias on a reaction-time task. Symptom-based depression subgroups did not predict these external variables. CONCLUSIONS: Neural connectivity-based categorization travels with diagnostic category and is clinically predictive, but not clinically deterministic. Both patients and control subjects showed heterogeneous, and overlapping, profiles. The larger and more severely affected patient subgroup was characterized by ventrally driven hyperconnectivity during positive processing. Data-driven parsing suggests heterogeneous substrates of depression and possible resilience in control subjects in spite of biological overlap.

Longitudinal Modeling of the Association Between Transmissible Risk, Affect During Drug Use and Development of Substance Use Disorder.

OBJECTIVE: This longitudinal investigation examined the hypothesis that subjective experience during consumption of preferred drugs mediates the association of transmissible risk for substance use disorder (SUD) measured in childhood and adolescence, and SUD diagnosis in adulthood. Transmissible risk denotes the psychological characteristics having intergenerational continuity between parents and their biological children. METHODS: The transmissible liability index (TLI) was administered to four hundred eighty-three 10 to 12-year-old boys (baseline). Follow-up evaluations were conducted when the boys attained 12-14, 16, 19, and 22 years of age, using age-specific versions of the TLI. Frequency of consumption of the participants' three most preferred drugs, affect on an ordinary day, affect while under influence of the preferred substances, and presence/absence of current SUD were assessed at 22 years of age. RESULTS: Consumption frequency of preferred drugs among boys mediates the association of transmissible risk during childhood, and adolescence and SUD diagnosis in adulthood. Severity of negative affect on a drug-free day predicts frequency of consumption of preferred drugs, which, in turn, predicts severity of negative affect during the drug use event. Neither affect on a drug-free day nor affect during the drug use event mediates the association of transmissible risk and SUD. CONCLUSIONS: Affect on drug-free days, and while under influence of preferred substances, covary with consumption frequency; however, affect is not related to transmissible SUD risk or SUD outcome.

Modeling the pharmacokinetic-pharmacodynamic relationship of the monoclonal anti-macaque-IL-15 antibody Hu714MuXHu in cynomolgus monkeys.

Hu714MuXHu is a recombinant chimeric murine-human monoclonal antibody directed against interleukin-15 (IL-15), a proinflammatory cytokine associated with memory CD8+ and natural killer (NK) T-cell activation and implicated in the pathogenesis of inflammatory diseases. A pharmacokinetic-pharmacodynamic (PK/PD) model was developed to describe the NK cell count reduction in cynomolgus monkeys after treatment with Hu714MuXHu. Cynomolgus monkeys were dosed with Hu714MuXHu in three studies: as a single dose at 0.1 or 1 mg·kg(-1) i.v.; weekly for 5 weeks at 0, 30, 60, or 150 mg·kg(-1) i.v. or 150 mg·kg(-1) s.c.; weekly for 13 weeks at 0, 5, 30, or 150 mg·kg(-1) s.c. Serum Hu714MuXHu concentration-time data were analyzed using noncompartmental analysis and the PK/NK cell count relationship was assessed via simultaneous PK/PD modeling. Hu714MuXHu PK was approximately dose-proportional between 0.1-150 mg·kg(-1) for i.v. and 5-150 mg·kg(-1) for s.c. administration with an elimination half-life of 12.7-18 days. Hu714MuXHu administration resulted in rapid and marked reductions in NK cell counts after the first dose which recovered fully after the serum Hu714MuXHu concentrations approached 0.1 µg·mL(-1) (assay limit of quantification). PK/PD modeled Hu714MuXHu effects on NK cells had an EC 50 of 0.09 µg·mL(-1). In summary, weekly i.v. or s.c. doses with Hu714MuXHu for up to 3 months in cynomolgus monkeys demonstrated linear PK and significant NK cell count reduction, which was described using PK/PD modeling. This approach may be used to guide investigative product dose selections for inflammatory diseases where NK cell count alterations are quantifiable.

Temperament disturbances measured in infancy progress to substance use disorder 20 years later.

OBJECTIVE: This prospective study determined whether temperament before two years of age predicts transmissible risk for substance use disorder (SUD) up to a decade later and SUD outcome in adulthood. METHOD: Boys between 10 and 12 years of age (N = 482) were tracked to age 22. The previously validated transmissible liability index (TLI) was administered at baseline, and temperament prior to two years of age was retrospectively rated. The Structured Clinical Interview for DSM-III-R (SCID) was administered to document presence/absence of SUD for parents at baseline and sons at age 22. RESULTS: Path analysis revealed that number of parents with SUD predicted severity of temperament disturbance in their sons which in turn predicted TLI score at age 10-12, presaging SUD. Temperament before age two did not predict SUD at age 22. The association between number of SUD parents and transmissible risk was mediated by severity of temperament disturbance. CONCLUSION: Temperament disturbance in early childhood, reflecting quality of behavioral and emotion regulation, comprise psychological antecedents of transmissible risk for SUD.

Externalizing behavior and emotion dysregulation are indicators of transmissible risk for substance use disorder.

BACKGROUND: Psychological items discriminating children of fathers diagnosed with an illicit drug-related substance use disorder and normal controls are indicators of a unidimensional construct termed transmissible liability index (TLI) (Vanyukov et al., 2009). TLI is a highly heritable (Vanyukov et al., 2009; Hicks, Iacono, McGue, 2012) and valid (Vanyukov et al., 2009; Hicks et al., 2009; Kirisci et al., 2013a) measure of childhood liability to substance use disorders (SUDs). AIMS: This longitudinal study determined whether TLI has incremental validity for predicting SUD beyond commonly measured psychological indicators of risk. METHODS: TLI and measures of executive cognitive capacity, emotion dysregulation and externalizing disturbance were administered to boys at ages 10-12 and 16. SUD outcome determined at age 22 was assessed as (1) any SUD, (2) the number of drug-specific SUDs, and (3) SUD severity. RESULTS: TLI predicted SUD beyond the contribution of measures of emotion dysregulation, executive cognitive capacity and externalizing disturbance. The association of emotion dysregulation and externalizing behavior at ages 10-12 and 16 with SUD at age 22 was also reduced to non-significance after controlling for transmissible risk measured by TLI. CONCLUSIONS: TLI's incremental validity beyond these latter indicators of risk points to its utility for identifying vulnerable youths requiring intervention.

C'mon get happy: reduced magnitude and duration of response during a positive-affect induction in depression.

BACKGROUND: Depression involves decreased positive affect. Whether this is due to a failure to achieve or maintain positive emotion in response to discrete stimuli is unclear. Understanding the nature of decreased positive affect could help to address how to intervene in the phenomenon, for example, how to structure interventions using positive and rewarding stimuli in depression. Thus, we examined the time course of affect following exposure to positive stimuli in depressed and healthy individuals. METHODS: Seventy-one adults with major depressive disorder and thirty-four never-depressed controls read a self-generated highly positive script and continuously rated their affect for 7 min. RESULTS: Both groups quickly achieved increased positive affect, however, compared to controls, depressed participants did not achieve the same level of positive affect, did not maintain their positive affect, spent less time rating their affect as happy, and demonstrated larger drops in mood. CONCLUSIONS: These data indicate that depressed and nondepressed individuals can generate positive reactions to happy scripts, but depressed individuals cannot achieve or sustain equivalent levels of positive affect. Interventions for depression might fruitfully focus on increasing depressed individuals' ability to maintain initial engagement with positive stimuli over a sustained period of time.

Homeostasis of human NK cells is not IL-15 dependent.

IL-15 is a proinflammatory cytokine that plays an important role in the development and activation of NK cells and is a potential target for inflammatory disease therapy. Studies conducted in IL-15- and IL-15R knockout mice identified IL-15 as an important cytokine for NK cell homeostasis. Consistent with this information derived from genetically modified mice, we demonstrated that neutralizing IL-15 with a mouse anti-mouse IL-15 mAb (M96) depletes C57BL/6 mouse NK cells. An mAb directed against macaque IL-15 (Hu714MuXHu) was manufactured and demonstrated to block IL-15-induced activation of nonhuman primate (NHP) NK cells in vitro. Neutralization of macaque IL-15 by parenteral administration of Hu714MuXHu reduces (>95%) circulating NK cell counts in NHPs. A blocking mAb directed against human IL-15 (huIL-15; AMG 714) was manufactured. Unexpectedly, when human subjects were treated with the blocking anti-IL-15 Ab AMG 714 in clinical trials, no reductions in circulating NK cell counts were observed despite achieving significantly higher exposures than the levels of Hu714MuXHu needed to cause NK cell count reductions in NHPs in vivo. Both AMG 714 and Hu714MuXHu are able to block huIL-15 activity in a human T cell blast proliferation and IFN-γ production assay. Both Abs block huIL-15-mediated Stat5 activation and CD69 expression in human NK cells. Collectively, these results demonstrate that NK cell homeostasis is obligatorily dependent upon IL-15 in both mice and NHPs, but that IL-15 is dispensable for maintenance of circulating human NK cells.

Modeling the association between sexual maturation, transmissible risk, and peer relationships during childhood and adolescence on development of substance use disorder in young adulthood.

BACKGROUND: This prospective study investigated pubertal timing and transmissible risk in relation to affiliation with deviant peers on the development of substance use disorder (SUD). METHOD: Participants were boys (N = 500) ascertained through proband fathers with (N = 250), and without (N = 250) DSM-III-R lifetime diagnosis of SUD who were prospectively tracked from age 10-12 to 22. Transmissible liability index (TLI), Tanner stage, peer delinquency, and substance use were measured at ages 10-12 and 16. SUD diagnosis during early adulthood was determined. RESULTS: Structural equation modeling revealed two pathways in which transmissible risk and sexual maturation influenced development of SUD. In the first pathway, transmissible risk was correlated with and prospectively predicted affiliation with deviant peers and substance use presaging SUD. In the second pathway, advanced sexual maturation positively predicted affiliation with deviant peers and substance use, which in turn predicted SUD. However, transmissible risk was not associated with pubertal development. CONCLUSION: These findings indicate that advanced sexual maturation and transmissible risk constitute unrelated facets of SUD liability; however, both factors bias development toward SUD via affiliation with deviant peers. SCIENTIFIC SIGNIFICANCE: Youth with advanced sexual maturation and/or transmissible risk for SUD are at higher risk for developing SUD. Additional research is needed to determine if addressing these risk factors will contribute to advancements in SUD prevention.

A novel assay to measure B cell responses to keyhole limpet haemocyanin vaccination in healthy volunteers and subjects with systemic lupus erythematosus.

The aim of the study was to characterize performance of a complementary set of assays to measure antigen-specific immune responses in subjects immunized with a neoantigen. Healthy volunteers (HV) (n = 8) and patients with systemic lupus erythematosus (SLE) (n = 6) were immunized with keyhole limpet haemocyanin (KLH) on days 1 and 29. Serum antibodies were detected using a flow cytometric bead array (CBA) that multiplexed the KLH response alongside pre-existing anti-tetanus antibodies. Peripheral blood mononuclear cells were studied by B cell ELISPOT. These assays were built upon precedent assay development in cynomolgus monkeys, which pointed towards their utility in humans. Primary anti-KLH IgG responses rose to a mean of 65-93-fold above baseline for HV and SLE patients, respectively, and secondary responses rose to a mean of 260-170-fold above baseline. High levels of anti-tetanus IgG were detected in pre-immunization samples and their levels did not change over the course of study. Anti-KLH IgG1-4 subclasses were characterized by a predominant IgG1 response, with no significant differences in subclass magnitude or distribution between HV and SLE subjects. Anti-KLH IgM levels were detectable, although the overall response was lower. IgM was not detected in two SLE subjects whodid generate an IgG response. All subjects responded to KLH by B cell ELISPOT, with no significant differences observed between HV and SLE subjects. The CBA and B cell ELISPOT assays reliably measured anti-KLH B cell responses, supporting use of this approach and these assays to assess the pharmacodynamic and potential safety impact of marketed/investigational immune-therapeutics.

Relation among HPA and HPG neuroendocrine systems, transmissible risk and neighborhood quality on development of substance use disorder: results of a 10-year prospective study.

BACKGROUND: Research has shown involvement of hormones of the hypothalamic pituitary adrenal (HPA) axis and hypothalamic pituitary gonadal (HPG) axis in the regulation of behaviors that contribute to SUD risk and its intergenerational transmission. Neighborhood environment has also been shown to relate to hormones of these two neuroendocrine systems and behaviors associated with SUD liability. Accordingly, it was hypothesized that (1) parental SUD severity and neighborhood quality correlate with activity of the HPG axis (testosterone level) and HPA axis (cortisol stability), and (2) transmissible risk during childhood mediates these hormone variables on development of SUD measured in adulthood. METHODS: Transmissible risk for SUD measured by the transmissible liability index (TLI; Vanyukov et al., 2009) along with saliva cortisol and plasma testosterone were prospectively measured in boys at ages 10-12 and 16. Neighborhood quality was measured using a composite score encompassing indicators of residential instability and economic disadvantage. SUD was assessed at age 22. RESULTS: Neither hormone variable cross-sectionally correlated with transmissible risk measured at ages 10-12 and 16. However, the TLI at age 10-12 predicted testosterone level and cortisol stability at age 16. Moreover, testosterone level, correlated with cortisol stability at age 16, predicted SUD at age 22. CONCLUSION: HPA and HPG axes activity do not underlie variation in TLI, however, high transmissible risk in childhood predicts neuroendocrine system activity presaging development of SUD.

Does the "gateway" sequence increase prediction of cannabis use disorder development beyond deviant socialization? Implications for prevention practice and policy.

BACKGROUND: This study was conducted to test whether non-normative socialization mediates the association between transmissible risk measured in childhood and cannabis use disorder manifested by young adulthood, and whether the sequence of drug use initiation ("gateway", i.e., consuming legal drugs before cannabis, or the reverse) increases accuracy of prediction of cannabis use disorder. METHODS: Sons of fathers with or without substance use disorders (SUDs) related to illicit drugs were tracked from 10-12 to 22 years of age to model the association between transmissible risk for SUD, socialization (peer deviance), order of drug use initiation ("gateway" or reverse sequence), and development of cannabis use disorder. Path analysis was used to evaluate relationships among the variables. RESULTS: Non-normative socialization mediates the association between transmissible risk measured during childhood and cannabis use disorder manifest by young adulthood. The sequence of drug use initiation did not contribute additional explanatory information to the model. CONCLUSIONS: The order of drug use initiation does not play a substantial role in the etiology of cannabis use disorder.

TREATMENT TRIAL AND LONG-TERM FOLLOW-UP EVALUATION AMONG COMORBID YOUTH WITH MAJOR DEPRESSION AND A CANNABIS USE DISORDER.

OBJECTIVE: This study compared the acute phase (12-week) and the long-term (1 year) efficacy of fluoxetine versus placebo for the treatment of the depressive symptoms and the cannabis use of youth with comorbid major depressive disorder (MDD) and an cannabis use disorder (CUD)(cannabis dependence or cannabis abuse). We hypothesized that fluoxetine would demonstrate efficacy in the acute phase trial and at the 1-year follow-up evaluation. Data is also provided regarding the prevalence of risky sexual behaviors in our study sample. METHODS: We recently completed the first double-blind placebo-controlled study of fluoxetine in adolescents and young adults with comorbid MDD/CUD. A total of 70 persons participated in the acute phase trial, and 68 of those persons (97%) also participated in the 1-year follow-up evaluation. Results of the acute phase study have already been presented (Cornelius, Bukstein, et al., 2010), but the results of the 1 year follow-up assessment have not been published previously. All participants in both treatment groups also received manual-based cognitive behavioral therapy (CBT) and motivation enhancement therapy (MET) during the 12-week course of the study. The 1-year follow-up evaluation was conducted to assess whether the clinical improvements noted during the acute phase trial persisted long term. RESULTS: During the acute phase trial, subjects in both the fluoxetine group and the placebo group showed significant within-group improvement in depressive symptoms and in cannabis-related symptoms. However, no significant difference was noted between the floxetine group and the placebo group on any treatment outcome variable during the acute phase trial. End of study levels of depressive symptoms were low in both the fluoxetine group and the placebo group. Most of the clinical improvements in depressive symptoms and for cannabis-related symptoms persisted at the 1-year follow-up evaluation. CONCLUSIONS: Fluoxetine did not demonstrate greater efficacy than placebo for treating either the depressive symptoms or the cannabis-related symptoms of our study sample during the acute phase study or at the 1-year follow-up assessment. The lack of a significant treatment effect for fluoxetine may at least in part reflect efficacy of the CBT/MET psychotherapy. A persistence of the efficacy of the acute phase treatment was noted at the 1-year follow-up evaluation, suggesting long-term effectiveness for the CBT/MET psychotherapy.

Quinolinone-based agonists of S1P1: use of a N-scan SAR strategy to optimize in vitro and in vivo activity.

We reveal how a N-scan SAR strategy (systematic substitution of each CH group with a N atom) was employed for quinolinone-based S1P(1) agonist 5 to modulate physicochemical properties and optimize in vitro and in vivo activity. The diaza-analog 17 displays improved potency (hS1P(1) RI; 17: EC(50)=0.020 µM, 120% efficacy; 5: EC(50)=0.070 µM, 110% efficacy) and selectivity (hS1P(3) Ca(2+) flux; 17: EC(50) >25 µM; 5: EC(50)=1.5 µM, 92% efficacy), as well as enhanced pharmacokinetics (17: CL=0.15 L/h/kg, V(dss)=5.1L/kg, T(1/2)=24h, %F=110; 5: CL=0.93L/h/kg, V(dss)=11L/kg, T(1/2)=15 h, %F=60) and pharmacodynamics (17: 1.0mg/kg po, 24h PLC POC=-67%; 5: 3mg/kg po, 24h PLC POC=-51%) in rat.

4-Methoxy-N-[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide: A Potent and Selective Agonist of S1P1.

The sphingosine-1-phosphate-1 receptor (S1P1) and its endogenous ligand sphingosine-1-phosphate (S1P) cooperatively regulate lymphocyte trafficking from the lymphatic system. Herein, we disclose 4-methoxy-N-[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide (8), an uncommon example of a synthetic S1P1 agonist lacking a polar headgroup, which is shown to effect dramatic reduction of circulating lymphocytes (POC = -78%) in rat 24 h after a single oral dose (1 mg/kg). The excellent potency that 8 exhibits toward S1P1 (EC50 = 0.035 µM, 96% efficacy) and the >100-fold selectivity that it displays against receptor subtypes S1P2-5 suggest that it may serve as a valuable tool to understand the clinical relevance of selective S1P1 agonism.

Benzofuran Derivatives as Potent, Orally Active S1P1 Receptor Agonists: A Preclinical Lead Molecule for MS.

We have discovered novel benzofuran-based S1P1 agonists with excellent in vitro potency and selectivity. 1-((4-(5-Benzylbenzofuran-2-yl)-3-fluorophenyl)methyl) azetidine-3-carboxylic acid (18) is a potent S1P1 agonist with >1000× selectivity over S1P3. It demonstrated a good in vitro ADME profile and excellent oral bioavailability across species. Dosed orally at 0.3 mg/kg, 18 significantly reduced blood lymphocyte counts 24 h postdose and demonstrated efficacy in a mouse EAE model of relapsing MS.