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Intentional forgetting of unwanted items is effortful, yet directed forgetting seems to improve when a secondary task is performed. According to the cognitive load hypothesis of directed forgetting, allocating attentional resources to another task improves forgetting by restricting unwanted encoding of to-be-forgotten (TBF) items. Alternatively, it might be that anything that makes studying more difficult will encourage greater effort to perform the task well and therefore lead to improved intentional forgetting. To assess these proposals we imposed data-processing limitations on study words in an item-method directed forgetting paradigm. Across six experiments, the perceptual quality of study words was manipulated by varying: (1) the duration of study word presentation (Experiments 1–4); (2) the contrast of the displayed word against its visual background (Experiment 5); or (3) the amount of visual background noise on which the word was presented (Experiment 6). In Experiments 4–6, a lexical decision task corroborated the difficulty of study word processing. Despite evidence that relatively low visual contrast and relatively high visual background noise, in particular, create challenging conditions, we found no evidence that perceptual quality impacts the magnitude of the directed forgetting effect. This work suggests that data limitations have no discernible effect on forgetting and corroborate that only attentional resource limitations improve directed forgetting.

Sphingosine-1-phosphate (S1P) binds to a family of sphingosine-1-phosphate G-protein-coupled receptors (S1P1-5). The interaction of S1P with these S1P receptors has a fundamental role in many physiological processes in the vascular and immune systems. Agonist-induced functional antagonism of S1P1 has been shown to result in lymphopenia. As a result, agonists of this type hold promise as therapeutics for autoimmune disorders. The previously disclosed differentiated S1P1 modulator BMS-986104 (1) exhibited improved preclinical cardiovascular and pulmonary safety profiles as compared to earlier full agonists of S1P1; however, it demonstrated a long pharmacokinetic half-life (T1/2 18 days) in the clinic and limited formation of the desired active phosphate metabolite. Optimization of this series through incorporation of olefins, ethers, thioethers, and glycols into the alkyl side chain afforded an opportunity to reduce the projected human T1/2 and improve the formation of the active phosphate metabolite while maintaining efficacy as well as the improved safety profile. These efforts led to the discovery of 12 and 24, each of which are highly potent, biased agonists of S1P1. These compounds not only exhibited shorter in vivo T1/2 in multiple species but are also projected to have significantly shorter T1/2 values in humans when compared to our first clinical candidate. In models of arthritis, treatment with 12 and 24 demonstrated robust efficacy.

This study embedded attentional cues in the study phase of an item-method directed forgetting task. We used an unpredictive onset cue (Experiment 1), a predictive onset cue (Experiment 2), or a predictive central cue (Experiments 3-6) to direct attention to the left or right. In Experiments 1-5, this was followed by a pink or blue study word that required a speeded colour discrimination; in Experiment 6, it was followed by a pink or blue word or nonword that required a lexical decision. Each study word was followed by an instruction to Remember or Forget. A yes-no recognition test confirmed better recognition of to-be-remembered words than to-be-forgotten words; a cueing effect confirmed the effectiveness of predictive cues in allocating attentional resources. There was, however, no evidence that the directed forgetting effect differed for attended and unattended words: Encoding depends more on the memory intention formed after a study word has disappeared than on the availability of processing resources when that word first appears.

[Image: see text] Efforts aimed at increasing the in vivo potency and reducing the elimination half-life of 1 and 2 led to the identification of aryl ether and thioether-derived bicyclic S1P(1) differentiated modulators 3–6. The effects of analogs 3–6 on lymphocyte reduction in the rat (desired pharmacology) along with pulmonary- and cardiovascular-related effects (undesired pharmacology) are described. Optimization of the overall properties in the aryl ether series yielded 3d, and the predicted margin of safety against the cardiovascular effects of 3d would be large enough for human studies. Importantly, compared to 1 and 2, compound 3d had a better profile in both potency (ED(50) < 0.05 mg/kg) and predicted human half-life (t(1/2) ∼ 5 days).

In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo-N1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo[1,2-b]pyridazine analogs were found to display dramatically improved metabolic stability. The N1-substituent on 2-oxo-1,2-dihydropyridine ring can be a variety of alkyl, aryl, and heteroaryl groups, but among them, 2-pyridyl provided much enhanced Caco-2 permeability, attributed to its ability to form intramolecular hydrogen bonds. Further structure-activity relationship studies at the C3 position led to the identification of highly potent and selective Tyk2 JH2 inhibitor 6, which proved to be highly effective in inhibiting IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis model.

Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P1 receptor modulator. In comparison to fingolimod (1), a full agonist of S1P1 currently marketed for the treatment of relapse remitting multiple sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in preclinical evaluations against undesired pulmonary and cardiovascular effects. In clinical trials, 2 was found to exhibit a pharmacokinetic half-life (T1/2) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P1. Herein, we describe our efforts to discover highly potent, partial agonists of S1P1 with a shorter T1/2 and increased in vivo phosphate metabolite formation. These efforts culminated in the discovery of BMS-986166 (14a), which was advanced to human clinical evaluation. The pharmacokinetic/pharmacodynamic (PK/PD) relationship as well as pulmonary and cardiovascular safety assessments ar...

Intentional forgetting of unwanted items is effortful, yet directed forgetting seems to improve when a secondary task is performed. According to the cognitive load hypothesis of directed forgetting, allocating attentional resources to another task improves forgetting by restricting unwanted encoding of to-be-forgotten (TBF) items. Alternatively, it might be that anything that makes studying more difficult will encourage greater effort to perform the task well and therefore lead to improved intentional forgetting. To assess these proposals we imposed data-processing limitations on study words in an item-method directed forgetting paradigm. Across six experiments, the perceptual quality of study words was manipulated by varying: (1) the duration of study word presentation (Experiments 1-4); (2) the contrast of the displayed word against its visual background (Experiment 5); or (3) the amount of visual background noise on which the word was presented (Experiment 6). In Experiments 4-6, a lexical decision task corroborated the difficulty of study word processing. Despite evidence that relatively low visual contrast and relatively high visual background noise, in particular, create challenging conditions, we found no evidence that perceptual quality impacts the magnitude of the directed forgetting effect. This work suggests that data limitations have no discernible effect on forgetting and corroborate that only attentional resource limitations improve directed forgetting.

Sphingosine-1-phosphate (S1P) binds to a family of sphingosine-1-phosphate G-protein-coupled receptors (S1P

[Image: see text] Bruton’s tyrosine kinase (BTK) has been shown to play a key role in the pathogenesis of autoimmunity. Therefore, the inhibition of the kinase activity of BTK with a small molecule inhibitor could offer a breakthrough in the clinical treatment of many autoimmune diseases. This Letter describes the discovery of BMS-986143 through systematic structure–activity relationship (SAR) development. This compound benefits from defined chirality derived from two rotationally stable atropisomeric axes, providing a potent and selective single atropisomer with desirable efficacy and tolerability profiles.

In an item-method directed forgetting task, attentional resources are withdrawn from forget item processing (e.g., Taylor & Fawcett in Attention, Perception, & Psychophysics, 73, 1790–1814, 2011). Taylor and Hamm (Attention, Perception, & Psychophysics, 78, 168–186, 2016) demonstrated that there is no corresponding increase in the proclivity for exogenous attention to be captured following a forget instruction. This means either that the attentional resources withdrawn from the forget item are reallocated immediately (and therefore not especially vulnerable to capture) or that it is not exogenous attention that is withdrawn. Given that endogenous attention is distinct from exogenous attention, we therefore extended the Taylor and Hamm study by using endogenous orienting rather than exogenous orienting. Words appeared individually in a peripheral location (Exp. 1) or in a central location (Exp. 2), followed by an instruction to either remember or forget. After a short (50-ms) or long (250-ms) interstimulus interval (ISI), a central cue (80% accurate) directed participants to allocate their attention to the left or right. This was followed by a discrimination target that appeared at a 1,000-ms cue–target stimulus onset asynchrony. A subsequent yes–no recognition test assessed memory for all study items. In both experiments, we observed better recognition of remember words than forget words—a directed forgetting effect. We also found a cueing effect, revealed as faster reaction times to discriminate cued targets than to discriminate uncued targets. There was not, however, an effect of memory instruction (and/or instruction–cue ISI) on the magnitude of this cueing effect. Thus, neither exogenous attention nor endogenous attention remains in an unengaged state following an instruction to forget.

Using an item-method directed forgetting task, we presented homographic homophonic nouns embedded in sentences. At study, each sentence was followed by an instruction to remember or forget the embedded word. On a subsequent yes-no recognition test, each word was again embedded within a sentence. In Experiments 1, 2, and 4 we varied the embedding sentence at test so that it was identical to that at study, changed but retained the meaning of the studied word, or changed to alter the meaning of the studied word. Repeated context - whether the sentence and/or the word meaning - proved to be as useful a retrieval cue for TBF items as for TBR items. In Experiment 3, we demonstrated that physical repetition was insufficient to produce context effects for either TBR or TBF items. And, in Experiment 4, we determined that participants were equally accurate in reporting context repetition/change following the correct recognition of TBR and TBF items. When considered in light of the existing literature, our results suggest that when context can be dissociated from the study item, it is encoded in "one shot" and not vulnerable to subsequent efforts to limit unwanted encoding.

This study used rapid serial visual presentation (RSVP) to determine whether, in an item-method directed forgetting task, study word processing ends earlier for forget words than for remember words. The critical manipulation required participants to monitor an RSVP stream of black nonsense strings in which a single blue word was embedded. The next item to follow the word was a string of red fs that instructed the participant to forget the word or green rs that instructed the participant to remember the word. After the memory instruction, a probe string of black xs or os appeared at postinstruction positions 1-8. Accuracy in reporting the identity of the probe string revealed an attenuated attentional blink following instructions to forget. A yes-no recognition task that followed the study trials confirmed a directed forgetting effect, with better recognition of remember words than forget words. Considered in the context of control conditions that required participants to commit either all or none of the study words to memory, the pattern of probe identification accuracy following the directed forgetting task argues that an intention to forget releases limited-capacity attentional resources sooner than an instruction to remember-despite participants needing to maintain an ongoing rehearsal set in both cases.

In an item-method directed forgetting paradigm, words are presented one at a time, each followed by an instruction to Remember or Forget; a directed forgetting effect is measured as better subsequent memory for Remember words than Forget words. The dominant view is that the directed forgetting effect arises during encoding due to selective rehearsal of Remember over Forget items. In three experiments we attempted to falsify a strong view that directed forgetting effects in recognition are due only to encoding mechanisms when an item method is used. Across 3 experiments we tested for retrieval-based processes by colour-coding the recognition test items. Black colour provided no information; green colour cued a potential Remember item; and, red colour cued a potential Forget item. Recognition cues were mixed within-blocks in Experiment 1 and between-blocks in Experiments 2 and 3; Experiment 3 added explicit feedback on the accuracy of the recognition decision. Although overall recognition improved with cuing when explicit test performance feedback was added in Experiment 3, in no case was the magnitude of the directed forgetting effect influenced by recognition cueing. Our results argue against a role for retrieval-based strategies that limit recognition of Forget items at test and posit a role for encoding intentions only.

Using an item-method directed forgetting task, we presented negative, neutral, and positive photographic pictures, one at a time, each followed by an instruction to remember or forget. We determined that the directed forgetting effect, defined as better subsequent recognition of to-be-remembered (TBR) items than to-be-forgotten (TBF) items, was equivalent across negative, neutral, and positive pictures. To disentangle the underlying costs (i.e., decrease in memory for TBF items) and benefits (i.e., increase in memory for TBR items), we compared recognition memory performance in the directed forgetting task to that of a novel within-subjects remember-all control condition (Experiment 1) and to a between-subjects remember-all control group (Experiment 2). We observed costs without benefits across all three emotions-negative, neutral, and positive-in both experiments. These results demonstrate that equivalent directed forgetting effects for emotional stimuli are not attributable to different underlying component processes. Instead, our results suggest that selection for encoding is accomplished in similar ways, regardless of emotional content.

Bruton’s tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fce receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.

Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P

Recently, our research group reported the identification of prodrug amino-alcohol 2 as a potent and efficacious S1P1 receptor modulator. This molecule is differentiated preclinically over the marketed drug fingolimod (Gilenya 1), whose active phosphate metabolite is an S1P1 full agonist, in terms of pulmonary and cardiovascular safety. S1P1 partial agonist 2, however, has a long half-life in rodents and was projected to have a long half-life in humans. The purpose of this communication is to disclose highly potent partial agonists of S1P1 with shorter half-lives relative to the clinical compound 2. PK/PD relationships as well as their preclinical pulmonary and cardiovascular safety assessment are discussed.

We describe a highly efficient route for the synthesis of 4a (BMS-986104). A key step in the synthesis is the asymmetric hydroboration of trisubstituted alkene 6. Particularly given the known difficulties involved in this type of transformation (6 → 7), the current methodology provides an efficient approach to prepare this class of compounds. In addition, we disclose the efficacy of 4a in a mouse EAE model, which is comparable to 4c (FTY720). Mechanistically, 4a exhibited excellent remyelinating effects on lysophosphatidylcholine (LPC) induced demyelination in a three-dimensional brain cell culture assay.

Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fce receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure–activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties an...

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates a multitude of physiological processes such as lymphocyte trafficking, cardiac function, vascular development, and inflammation. Because of the ability of S1P1 receptor agonists to suppress lymphocyte egress, they have great potential as therapeutic agents in a variety of autoimmune diseases. In this article, the discovery of selective, direct acting S1P1 agonists utilizing an ethanolamine scaffold containing a terminal carboxylic acid is described. Potent S1P1 agonists such as compounds 18a and 19a which have greater than 1000-fold selectivity over S1P3 are described. These compounds efficiently reduce blood lymphocyte counts in rats through 24 h after single doses of 1 and 0.3 mpk, respectively. Pharmacodynamic properties of both compounds are discussed. Compound 19a was further studied in two preclinical models of disease, exhibiting good efficacy in both the rat adjuvant arthritis model (AA) and the mouse experimental autoimmune encephalomyelitis model (EAE).

[Image: see text] In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo-N1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo[1,2-b]pyridazine analogs were found to display dramatically improved metabolic stability. The N1-substituent on 2-oxo-1,2-dihydropyridine ring can be a variety of alkyl, aryl, and heteroaryl groups, but among them, 2-pyridyl provided much enhanced Caco-2 permeability, attributed to its ability to form intramolecular hydrogen bonds. Further structure–activity relationship studies at the C3 position led to the identification of highly potent and selective Tyk2 JH2 inhibitor 6, which proved to be highly effective in inhibiting IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis model.

Clinical validation of S1P receptor modulation therapy was achieved with the approval of fingolimod (Gilenya, 1) as the first oral therapy for relapsing remitting multiple sclerosis. However, 1 causes a dose-dependent reduction in the heart rate (bradycardia), which occurs within hours after first dose. We disclose the identification of clinical compound BMS-986104 (3d), a novel S1P1 receptor modulator, which demonstrates ligand-biased signaling and differentiates from 1 in terms of cardiovascular and pulmonary safety based on preclinical pharmacology while showing equivalent efficacy in a T-cell transfer colitis model.

We investigated whether intentional forgetting impacts only the likelihood of later retrieval from long-term memory or whether it also impacts the fidelity of those representations that are successfully retrieved. We accomplished this by combining an item-method directed forgetting task with a testing procedure and modeling approach inspired by the delayed-estimation paradigm used in the study of visual short-term memory (STM). Abstract or concrete colored images were each followed by a remember (R) or forget (F) instruction and sometimes by a visual probe requiring a speeded detection response (E1-E3). Memory was tested using an old-new (E1-E2) or remember-know-no (E3) recognition task followed by a continuous color judgment task (E2-E3); a final experiment included only the color judgment task (E4). Replicating the existing literature, more "old" or "remember" responses were made to R than F items and RTs to postinstruction visual probes were longer following F than R instructions. Color judgments were more accurate for successfully recognized or recollected R than F items (E2-E3); a mixture model confirmed a decrease to both the probability of retrieving the F items as well as the fidelity of the representation of those F items that were retrieved (E4). We conclude that intentional forgetting is an effortful process that not only reduces the likelihood of successfully encoding an item for later retrieval, but also produces an impoverished memory trace even when those items are retrieved; these findings draw a parallel between the control of memory representations within working and long-term memory.

In search for prodrugs to address the issue of pH-dependent solubility and exposure associated with 1 (BMS-582949), a previously disclosed phase II clinical p38α MAP kinase inhibitor, a structurally novel clinical prodrug, 2 (BMS-751324), featuring a carbamoylmethylene linked promoiety containing hydroxyphenyl acetic acid (HPA) derived ester and phosphate functionalities, was identified. Prodrug 2 was not only stable but also water-soluble under both acidic and neutral conditions. It was effectively bioconverted into parent drug 1 in vivo by alkaline phosphatase and esterase in a stepwise manner, providing higher exposure of 1 compared to its direct administration, especially within higher dose ranges. In a rat LPS-induced TNFα pharmacodynamic model and a rat adjuvant arthritis model, 2 demonstrated similar efficacy to 1. Most importantly, it was shown in clinical studies that prodrug 2 was indeed effective in addressing the pH-dependent absorption issue associated with 1.

Bruton’s tyrosine kinase (BTK) regulates critical signal transduction pathways involved in the pathobiology of rheumatoid arthritis (RA) and other autoimmune disorders. BMS-986142 is a potent and highly selective reversible small molecule inhibitor of BTK currently being investigated in clinical trials for the treatment of both RA and primary Sjogren’s syndrome. In the present report, we detail the in vitro and in vivo pharmacology of BMS-986142 and show this agent provides potent and selective inhibition of BTK (IC50 = 0.5 nM), blocks antigen receptor-dependent signaling and functional endpoints (cytokine production, co-stimulatory molecule expression, and proliferation) in human B cells (IC50 ≤ 5 nM), inhibits Fcγ receptor-dependent cytokine production from peripheral blood mononuclear cells, and blocks RANK-L-induced osteoclastogenesis. Through the benefits of impacting these important drivers of autoimmunity, BMS-986142 demonstrated robust efficacy in murine models of rheumatoid arthritis (RA), including collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA). In both models, robust efficacy was observed without continuous, complete inhibition of BTK. When a suboptimal dose of BMS-986142 was combined with other agents representing the current standard of care for RA (e.g., methotrexate, the TNFα antagonist etanercept, or the murine form of CTLA4-Ig) in the CIA model, improved efficacy compared to either agent alone was observed. The results suggest BMS-986142 represents a potential therapeutic for clinical investigation in RA, as monotherapy or co-administered with agents with complementary mechanisms of action.

In the item-method directed-forgetting paradigm, the magnitude of inhibition of return (IOR) is larger after an instruction to forget (F) than after an instruction to remember (R). In the present experiments, we further investigated this increased magnitude of IOR after F as compared to R memory instructions (dubbed the F > R IOR difference), in order to understand both the consequences for information processing and the purpose of the differential withdrawal of attention that results in this difference. Words were presented in one of four peripheral locations, followed by either an F or an R memory instruction. Then, a target appeared in either the same location as the previous word or one of the other locations. The results showed that the F > R IOR difference cannot be explained by attentional momentum (Exp. 1), that the spatial compatibility of the response options with target locations is not necessary for the F > R IOR difference to emerge (Exp. 2), and that the F > R IOR difference is location-specific rather than response-specific (Exp. 3). These results are consistent with the view that F > R IOR represents a bias against responding to information emanating from an unreliable source (Taylor & Fawcett, 2011).

The production effect is the finding that subsequent memory is better for words that are produced than for words that are not produced. Whereas the current literature demonstrates that reading aloud is the most effective form of production, the distinctiveness account used to explain the production effect predicts that there is nothing special about reading aloud per se: Other forms of vocal production that include an additional distinct element should produce even greater subsequent memory benefits than reading aloud. To test this, we presented participants with study words that they were instructed to read aloud loudly, read aloud, or read silently (Experiment 1); sing, read aloud, or read silently (Experiment 2); and sing, read aloud loudly, read aloud, or read silently (Experiment 3). We observed that both reading items aloud loudly (Experiments 1 and 3) and singing items (Experiments 2 and 3) at study resulted in greater subsequent recognition than reading items aloud in a normal voice; singing had a larger memory benefit than reading aloud loudly (Experiment 3). Our findings support the distinctiveness hypothesis by demonstrating that there are other forms of production, such as singing and reading aloud loudly that have a more pronounced effect on memory than reading aloud.

Videos were presented depicting events such as baking cookies or cleaning a fish tank. Periodically, the video paused and an instruction to Remember (R) or Forget (F) the preceding video segment was presented; the video then resumed. Participants later responded more accurately to cued-recall questions (E1) and to true/false statements (E2–5) regarding R segments than F segments. This difference was larger for specific information (the woman added 3 cups of flour) than for general information (the woman added flour). Participants were also slower to detect visual probes presented following F instructions compared to those presented following R instructions. These findings suggest that intentional forgetting is an effortful process that can be performed even on segments of otherwise continuous events and that the result is a relatively impoverished representation of the unwanted information in memory.

In a novel event method directed forgetting task, instructions to Remember (R) or Forget (F) were integrated throughout the presentation of four videos depicting common events (e.g., baking cookies). Participants responded more accurately to cued recall questions (E1) and true/false statements (E2-4) regarding R segments than F segments. This was true even when forced to attend to F segments by virtue of having to perform concurrent discrimination (E2) or conceptual segmentation (E3) tasks. The final experiment (E5) demonstrated a larger R >F difference for specific true/false statements (the woman added three cups of flour) than for general true/false statements (the woman added flour) suggesting that participants likely encoded and retained at least a general representation of the events they had intended to forget, even though this representation was not as specific as the representation of events they had intended to remember.

We describe a highly efficient route for the synthesis of 4a (BMS-986104). A key step in the synthesis is the asymmetric hydroboration of trisubstituted alkene 6. Particularly given the known difficulties involved in this type of transformation (6 → 7), the current methodology provides an efficient approach to prepare this class of compounds. In addition, we disclose the efficacy of 4a in a mouse EAE model, which is comparable to 4c (FTY720). Mechanistically, 4a exhibited excellent remyelinating effects on lysophosphatidylcholine (LPC) induced demyelination in a three-dimensional brain cell culture assay.

Fingolimod (1) is the first approved oral therapy for the treatment of relapsing remitting multiple sclerosis. While the phosphorylated metabolite of fingolimod was found to be a nonselective S1P receptor agonist, agonism specifically of S1P

Bruton’s tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure–activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide 6 (BMS-935177) was selected to advance into clinical development.

Items that are produced (e.g., read aloud) during encoding typically are better remembered than items that are not produced (e.g., read silently). This "production effect" has been explained by distinctiveness: Produced items have more distinct features than nonproduced items, leading to enhanced retrieval. The goal of the current study was to use electroencephalography (EEG) to examine the neural basis of the production effect. During study, participants were presented with words that they were required to read silently, read aloud, or sing while EEG data were recorded. Subsequent memory performance was tested using a yes/no recognition test. Analysis focused on the event-related brain potentials (ERPs) evoked by the encoding instruction cue for each instruction condition. Our data revealed enhanced memory performance for produced items and a greater P300 ERP amplitude for instructions to sing or read aloud compared with instructions to read silently. Our results demonstrate that the amplitude of the P300 is modulated by at least 1 aspect of production, vocalization (singing/reading aloud relative to reading silently), and are consistent with the distinctiveness account of the production effect. The ERP methodology is a viable tool for investigating the production effect. (PsycINFO Database Record

Sphingosine 1-phosphate (S1P) is the endogenous ligand for the sphingosine 1-phosphate receptors (S1P1–5) and evokes a variety of cellular responses through their stimulation. The interaction of S1P with the S1P receptors plays a fundamental physiological role in a number of processes including vascular development and stabilization, lymphocyte migration, and proliferation. Agonism of S1P1, in particular, has been shown to play a significant role in lymphocyte trafficking from the thymus and secondary lymphoid organs, resulting in immunosuppression. This article will detail the discovery and SAR of a potent and selective series of isoxazole based full agonists of S1P1. Isoxazole 6d demonstrated impressive efficacy when administered orally in a rat model of arthritis and in a mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.

The synthesis and structure–activity relationship (SAR) of a series of pyridyl-isoxazole based agonists of S1P1 are discussed. Compound 5b provided potent in vitro activity with selectivity, had an acceptable pharmacokinetic profile, and demonstrated efficacy in a dose dependent manner when administered orally in a rodent model of arthritis.

Three experiments explored the interaction between the production effect (greater memory for produced compared to non-produced study items) and the picture superiority effect (greater memory for pictures compared to words). Pictures and words were presented in a blocked (E1) or mixed (E2, E3) design, each accompanied by an instruction to silently name (non-produced condition) or quietly mouth (produced condition) the corresponding referent. Memory was then tested for all study items as well as an equal number of foil items using a speeded (E1, E2) or self-paced (E3) yes-no recognition task. Experiments 1, 2, and 3 all revealed a small but reliable production × stimulus interaction. Production was also found to result in a liberal shift in response bias that could result in the overestimation of the production effect when measured using hits instead of sensitivity. Together our findings suggest that the application of multiple distinctive processes at study produces an especially discriminative memory trace at test, more so than the summation of each process individually.

In an item-method directed forgetting paradigm, participants were required to attend to one of two colored words presented on opposite sides of a central fixation stimulus; they were instructed to Remember or Forget the attended item. On a subsequent recognition test, the Attended words showed a typical directed forgetting effect with better recognition of Remember words than Forget words. Our interest was in the fate of the Unattended words. When the study display disappeared before the memory instruction, there was no effect of that instruction on unattended words; when the study display remained visible during presentation of the memory instruction, there was a reverse directed forgetting effect with better recognition of unattended words from Forget trials than from Remember trials. Incidental encoding of task-irrelevant stimuli occurs following presentation of a Forget instruction – but only when those task-irrelevant stimuli are still visible in the external environment.

We combined an item-method directed forgetting paradigm with a secondary task requiring a response to discriminate the color of probe words presented 1400 ms, 1800 ms or 2600 ms following each study phase memory instruction. The speed to make the color discrimination was used to assess the cognitive demands associated with instantiating Remember (R) and Forget (F) instructions; incidental memory for probe words was used to assess whether instantiating an F instruction also affects items presented in close temporal proximity. Discrimination responses were slower following F than R instructions at the two longest intervals. Critically, at the 1800 ms interval, incidental probe word recognition was worse following F than R instructions, particularly when the study word was successfully forgotten (as opposed to unintentionally remembered). We suggest that intentional forgetting is an active cognitive process associated with establishing control over the contents of working memory.

We report the characterization of BMS-911543, a potent and selective small-molecule inhibitor of the Janus kinase (JAK) family member, JAK2. Functionally, BMS-911543 displayed potent anti-proliferative and pharmacodynamic (PD) effects in cell lines dependent upon JAK2 signaling, and had little activity in cell types dependent upon other pathways, such as JAK1 and JAK3. BMS-911543 also displayed anti-proliferative responses in colony growth assays using primary progenitor cells isolated from patients with JAK2(V617F)-positive myeloproliferative neoplasms (MPNs). Similar to these in vitro observations, BMS-911543 was also highly active in in vivo models of JAK2 signaling, with sustained pathway suppression being observed after a single oral dose. At low dose levels active in JAK2-dependent PD models, no effects were observed in an in vivo model of immunosuppression monitoring antigen-induced IgG and IgM production. Expression profiling of JAK2(V617F)-expressing cells treated with diverse JAK2 inhibitors revealed a shared set of transcriptional changes underlying pharmacological effects of JAK2 inhibition, including many STAT1-regulated genes and STAT1 itself. Collectively, our results highlight BMS-911543 as a functionally selective JAK2 inhibitor and support the therapeutic rationale for its further characterization in patients with MPN or in other disorders characterized by constitutively active JAK2 signaling.

Results of research investigating the link between anxiety sensitivity (AS) and memory biases toward threat have been inconsistent. There may be subgroups of high AS individuals who differ in their preferred mode of attending to threat-related information, thereby impacting memory. The impact of individual attention style on intentional forgetting of words varying in emotional valence was examined among individuals with varying levels of AS. By incorporating an inhibition of return (IOR) task (to yield a proxy of attentional allocation) within the study phase of the item-method directed forgetting paradigm, we categorized high, moderate, and low AS individuals according to their attention style in response to threat stimuli: ‘threat attenders’ (small IOR effect) and ‘threat avoiders’ (large IOR effect). Among high AS individuals only, ‘threat avoiders’ showed greater intentional forgetting of threat-related words than ‘threat attenders’. High AS ‘threat avoiders’ also had higher levels of anxiety-related psychopathology (AS and health anxiety) than high AS ‘threat attenders’.

Research has shown that the Simon effect is larger for targets suffering from inhibition of return (IOR). We used speed-accuracy trade-off (SAT) methodology to explore the temporal dynamics underlying this interaction. In Experiment 1, a new method for sorting the data was used to reveal a monotonic decay in the impact of task-irrelevant location information that is responsible for the Simon effect. In Experiment 2, we show that IOR delays both task-relevant identity and task-irrelevant location codes; a relatively longer delay for location than identity codes accounts for the effect of IOR on the Simon effect. When location information was made task-relevant in Experiment 3, IOR delayed the accumulation of this information by about the same amount as when location was irrelevant. The results suggest that IOR, therefore, has a greater effect on location than identity information.

Reaction time (RT) was measured in response to visual detection probes embedded within an item-method directed forgetting paradigm. In Experiment 1, study words were presented individually followed by an instruction to remember (R) or forget (F). Probes were presented at stimulus onset asynchronies (SOAs) of 1,400, 1,800, or 2,600 msec in relation to the study word or memory instruction. After the study trials, a yes-no recognition task measured retention of R and F words. Experiment 2 added a no-word control condition and no-probe catch trials. In both experiments, post-F probe RTs were longer than post-R probe RTs at early SOAs. Confirming that participants attended to the memory instructions, there was a significant directed forgetting effect, with greater recognition of R than of F words. These findings contradict the view that directed forgetting in the item-method paradigm is due to the passive decay of nonrehearsed F items; instead, they are consistent with the view that intentional forgetting in an item-method paradigm occurs via the operation of an active, potentially inhibitory, cognitive process.

A novel structural class of p38alpha MAP kinase inhibitors has been identified via iterative SAR studies of a focused deck screen hit. Optimization of the lead series generated 6e, BMS-640994, a potent and selective p38alpha inhibitor that is orally efficacious in rodent models of acute and chronic inflammation.

Inhibition of return (IOR) refers to slower reaction times (RTs) to targets that occur in the same, rather than in a different, location as a preceding onset cue. The present study examined IOR for expected (likely) and unexpected (unlikely) targets under conditions in which stimulus-response (S-R) expectancies were generated on a trial-by-trial basis or maintained across a block of trials. Three boxes were aligned along the vertical midline. In Experiments 1 and 2, the appearance of a cue in the upper or lower box was a signal to generate an expectancy about the most likely color of an impending discrimination target. In Experiment 3, one target color was more likely than another across a block of trials. In all cases, cue location did not predict target location. When S-R expectancies were generated on a trial-by-trial basis, IOR occurred for Unlikely targets but not for Likely targets; this was true across a range of cue-target stimulus onset asynchronies. In contrast, when S-R expectancies were maintained over a block of trials, IOR was larger for Likely than for Unlikely targets. These findings reveal a critical interaction of S-R expectancies with IOR. This interaction not only demonstrates the modulation of IOR by cognitive expectancies, but in doing so also provides evidence that is consistent with the view that IOR reflects a conservative response bias.

We measured attentional orienting in an item-method-directed forgetting task. Words appeared singly, followed by an instruction to remember or forget. In Experiment 1, study words appeared at center; in Experiments 2 and 3, they appeared to the left and right. In all three experiments, there was a delay of 50 ms or 250 ms, after which a cue appeared to the left or right of fixation. This was followed at a fixed 100-ms stimulus onset asynchrony by a target in the cued or uncued location. Attentional capture was measured by evaluating the speed to localize (Experiments 1 and 2) or discriminate (Experiment 3) targets in cued versus uncued locations. A subsequent yes-no recognition test confirmed a directed forgetting effect. Even though attention is purported to withdraw more readily after forget instructions than after remember instructions, we obtained no evidence for the corollary: Attention is not more readily captured by events that follow forget instructions. A forget instruction must therefore impact attention only insofar as withdrawal is needed to instantiate the intention to forget, without instigating a longer lasting distractibility.

Inhibition of return (10R) refers to a mechanism that slows response times (RTs) to detect, localize, or discriminate a target that is presented at a location previously occupied by an irrelevant peripheral cue. Generally, the slowing of RTs is described as a negative effect on responding that is believed to promote searching to new locations. In this report, we consider whether IOR might benefit performance when the goal is to prevent a prepared response. Using the stop-signal paradigm, we show that IOR improved the ability to inhibit a prepared response by delaying responses to the target. Thus, in addition to aiding visual search, IOR may also provide an opportunity for the adjustment of decisions and behaviour in accordance with the demands of a dynamic environment.

Inhibition of return (IOR) refers to slowed responding to a target that appears in the same rather than in a different location as a preceding peripheral onset cue. This study examined IOR as a function of whether the peripheral onset cue was a word that participants were directed to remember or forget. Using a modified item-method directed forgetting paradigm, words appeared one at a time to the left or right, followed by a remember or forget instruction. A target dot was then presented either in the same peripheral location as the preceding word or in a different location; participants made a speeded response to localize this target. Confirming compliance with the memory instructions, recall tests that alternated with blocks of IOR trials (Experiment 1) revealed few intrusions of to-be-forgotten words, and a final recognition test (Experiments 1 and 3) revealed more hits for to-be-remembered words than for to-be-forgotten words. Reaction times to the target dot revealed greater magnitude IOR following to-be-forgotten words than following to-be-remembered words (Experiments 1 and 3). Moreover, when compared to baseline IOR values (Experiment 2), it appeared that this difference resulted from a magnification of IOR following forget instructions and a reduction in IOR following remember instructions. These results demonstrate the usefulness of IOR as an index of memorial processes and suggest that attentional orienting may play a role in the remembering and forgetting of words presented in peripheral visual locations.

Inhibition of return (IOR) refers to slower responding to a stimulus that appears in the same rather than a different location as that of a preceding stimulus. The goal of the present study was to examine the relationship between IOR and stop signal inhibition. Participants were presented with two stimuli (S1 and S2) on each trial. On half of the trials (go trials), participants were required to make a speeded button-press response to report the location of S1; on the other half of trials (stop trials), they were required to cancel the response to S1, as indicated by the appearance of a stop signal at a variable delay (stop signal delay, SSD) after the appearance of S1. Success in cancelling an S1 response varied directly as a function of the SSD: The longer the delay, the more difficult it was for participants to cancel the prepared response. We examined the magnitude of IOR in the S2 reaction times as a function of whether participants made a correct go response to S1, made an erroneous non-cancelled response to S1, or successfully cancelled a response to S1. Our results indicated that the presentation of a stop signal increased the magnitude of IOR, even when the S1 response was not successfully cancelled. However, this was true only when the to-be-cancelled response involved the same effectors as the response used to reveal IOR. These results suggest that there may be a motor component to IOR that is sensitive to the same inhibitory processes that are used to cancel responses in a stop signal paradigm.

In the item-method directed forgetting paradigm, the magnitude of inhibition of return (IOR) is larger after an instruction to forget (F) than after an instruction to remember (R). In the present experiments, we further investigated this increased magnitude of IOR after F than after R memory instructions, to determine whether this F > R IOR pattern occurs only for the motoric form of IOR, as predicted, or also for the visual form. In three experiments, words were presented in one of two peripheral locations, followed by either an F or an R memory instruction. Then, a target appeared either at the same location as the previous word or at the other location. In Experiment 1, participants maintained fixation throughout the trial until the target appeared, at which point they made a saccade to the target. In Experiment 2, they maintained fixation throughout the entire trial and made a manual localization response to the target. The F > R IOR difference in reaction times occurred for both the saccadic and manual responses, suggesting that memory instructions modify both motoric and visual forms of IOR. In Experiment 3, participants made a perceptual discrimination response to report the identity of a target while the eyes remained fixed. The F > R IOR difference also occurred for these manual discrimination responses, increasing our confidence that memory instructions modify the visual form of IOR. We relate our findings to postulated differences in attentional withdrawal following F and R instructions and consider the implications of the findings for successful forgetting.