Global reactivity models are impactful in industrial synthesis applications.

Artificial Intelligence is revolutionizing many aspects of the pharmaceutical industry. Deep learning models are now routinely applied to guide drug discovery projects leading to faster and improved findings, but there are still many tasks with enormous unrealized potential. One such task is the reaction yield prediction. Every year more than one fifth of all synthesis attempts result in product yields which are either zero or too low. This equates to chemical and human resources being spent on activities which ultimately do not progress the programs, leading to a triple loss when accounting for the cost of opportunity in time wasted. In this work we pre-train a BERT model on more than 16 million reactions from 4 different data sources, and fine tune it to achieve an uncertainty calibrated global yield prediction model. This model is an improvement upon state of the art not just from the increase in pre-train data but also by introducing a new embedding layer which solves a few limitations of SMILES and enables integration of additional information such as equivalents and molecule role into the reaction encoding, the model is called BERT Enriched Embedding (BEE). The model is benchmarked on an open-source dataset against a state-of-the-art synthesis focused BERT showing a near 20-point improvement in r2 score. The model is fine-tuned and tested on an internal company data benchmark, and a prospective study shows that the application of the model can reduce the total number of negative reactions (yield under 5%) ran in Janssen by at least 34%. Lastly, we corroborate the previous results through experimental validation, by directly deploying the model in an on-going drug discovery project and showing that it can also be used successfully as a reagent recommender due to its fast inference speed and reliable confidence estimation, a critical feature for industry application.

One-Pot Reductive Alkylation of 2,4-Dihydroxy Quinolines and Pyridines.

A one-pot, Hantzsch ester-mediated Knoevenagel condensation-reduction reaction has been developed for alkylation of a wide range of substituted 2,4-quinoline diols and 2,4-pyridine diols with aldehydes. The process is operationally simple to perform, scalable, and provides highly useful C-3 alkylated quinoline and pyridine diols in yields of 58-92%. The alkylation products can be converted to 2,4-dihaloquinoline and pyridine substrates for further functionalization.

Social Problem Solving and Posttraumatic Growth New Possibilities in Postoperative Breast Cancer Survivors.

The purpose of this study was to examine whether social problem solving (SPS) would relate to posttraumatic growth (PTG), particularly new life possibilities in breast cancer survivors. Participants included 85 women who had undergone surgical intervention for breast cancer at least 6 months prior to study participation. Participant ages ranged from 29 to 88 years. The majority of the sample was White (86%), married (58%), and had received at least some postsecondary education (73%), and all participants spoke English. This IRB-approved cross-sectional study was part of a larger study examining psychosocial protective and risk factors in breast cancer survivors at a university-affiliated private hospital. We hypothesized that better SPS ability would relate to PTG new possibilities above and beyond age, annual income, and time since surgery. Results from this study indicate that a positive problem orientation and lack of impulsive/careless problem-solving style appear to play a role in posttraumatic growth among breast cancer survivors, particularly in developing beliefs about one's ability to positively change one's life. Given the established benefits of active/approach coping in cancer populations, it makes sense that similar interventions such as problem-solving therapy, a cognitive-behavioral therapy that includes challenging and reframing negative beliefs about self and situation, may promote new possibility beliefs in this population.

Family needs at a post-acute rehabilitation setting and suggestions for supports.

OBJECTIVE: To explore the perceived needs, obstacles to services, psychological distress and social problem-solving abilities of family members of persons with ABI at a post-acute community-based brain injury rehabilitation facility and offer suggestions for methods of assessment and providing support. PARTICIPANTS: Twenty-nine family members who did not provide daily care, but were involved in the care process. DESIGN: Participants completed self-report questionnaires including the FNQ:R, SOS, DASS-21, WHO-QOL BREF and SPSI:R-S. RESULTS: Participants reported informational and professional needs as most met and involvement in care, instrumental support and emotional support as most unmet. Most were satisfied with the amount of professional help and services and had confidence in the quality of care. Nearly half of the family members felt there were few ABI-related resources in the community and one third were unaware of good ABI treatment resources in their community. Psychosocial functioning was generally average. CONCLUSION: Family members who do not provide daily care are still impacted by the neurobehavioural changes that progress throughout the long-term, post-acute community phase. This study offers suggestions regarding an effective methodology for assessing family needs and recommends accessible and practical supports.

College students' use of energy drinks, social problem-solving, and academic performance.

Energy drink (ED) use among college students to improve academic performance (AP) has skyrocketed. A growing body of literature indicates that the risks associated with ED use may outweigh the perceived benefits. In this study, 486 undergraduates were surveyed on their general substance and ED usage, Social Problem-Solving (SPS) ability, and AP. It was hypothesized that: (1) ED use would be a negative predictor of AP; (2) SPS would be a positive predictor of AP; (3) SPS would be a negative predictor of ED use; and (4) SPS and ED use would account for a significant amount of the variance in AP. A linear multiple regression for AP was conducted, with predictor variables entered in the following order: total drug use, non-ED caffeine use, SPS, and ED use. The overall model was significant and accounted for approximately 7% of the variance in AP. The hypotheses of the study were supported, indicating that ED use may be related to decreased AP, SPS ability may be related to increased AP, or that students with poor AP and less effective SPS skills are more likely to use EDs. Implications of these findings are important for college students and other users of ED products.

The relationship between emotion regulation difficulties and psychopathic personality characteristics.

The factors of psychopathy assessment tools diverge in their relationships with numerous problematic behaviors and psychological disorders. Emotion dysregulation is a pathological process argued to cut across diagnoses, and may be important in better understanding these divergent associations. This study sought to clarify psychopathy's association with emotion regulation difficulties. It was predicted that the Fearless Dominance and Self-Centered Impulsivity factors of the Psychopathic Personality Inventory-Revised would demonstrate differential relationships with a multidimensional conceptualization of emotion regulation difficulties. Ninety-one male undergraduate students and 28 male court-mandated anger management participants completed self-report questionnaires measuring emotion regulation difficulties and psychopathic personality characteristics. Hierarchical regression analyses indicated that emotion regulation difficulties were negatively associated with Fearless Dominance psychopathic traits, but positively associated with Self-Centered Impulsivity and global psychopathic traits. In addition, emotion regulation difficulties explained incremental variance in psychopathic traits over and above negative affect alone. These findings may have clinical implications for the etiology and treatment of psychopathic personality disorder.

The influence of uncertainty and social support on information seeking concerning illicit stimulant use among young adults.

Using the Theory of Motivated Information Management (TMIM) and the concept of desired informational support as a framework, this project examined factors in the information management process young adults employ in potential information seeking about illicit stimulant drug use with members of their social networks. One hundred and seventy-three individuals participated in the study. Results indicated that (a) uncertainty discrepancy and the desire for informational support covaried, and (b) uncertainty discrepancy, anxiety, and outcome expectancy had significant impacts on the efficacy judgments made by individuals with regard to potential information seeking with their social networks about their stimulant drug use. The study thus provides further evidence for the utility of TMIM as a framework for understanding health communication in regard to drug use, and suggests that desired informational support may be a useful addition to the model for this health issue.

Reading visual braille with a retinal prosthesis.

Retinal prostheses, which restore partial vision to patients blinded by outer retinal degeneration, are currently in clinical trial. The Argus II retinal prosthesis system was recently awarded CE approval for commercial use in Europe. While retinal prosthesis users have achieved remarkable visual improvement to the point of reading letters and short sentences, the reading process is still fairly cumbersome. This study investigates the possibility of using an epiretinal prosthesis to stimulate visual braille as a sensory substitution for reading written letters and words. The Argus II retinal prosthesis system, used in this study, includes a 10 × 6 electrode array implanted epiretinally, a tiny video camera mounted on a pair of glasses, and a wearable computer that processes the video and determines the stimulation current of each electrode in real time. In the braille reading system, individual letters are created by a subset of dots from a 3 by 2 array of six dots. For the visual braille experiment, a grid of six electrodes was chosen out of the 10 × 6 Argus II array. Groups of these electrodes were then directly stimulated (bypassing the camera) to create visual percepts of individual braille letters. Experiments were performed in a single subject. Single letters were stimulated in an alternative forced choice (AFC) paradigm, and short 2-4-letter words were stimulated (one letter at a time) in an open-choice reading paradigm. The subject correctly identified 89% of single letters, 80% of 2-letter, 60% of 3-letter, and 70% of 4-letter words. This work suggests that text can successfully be stimulated and read as visual braille in retinal prosthesis patients.

Maternal child feeding practices and eating behaviors of women with extreme obesity and those who have undergone bariatric surgery.

BACKGROUND: Bariatric surgery is the most effective treatment of extreme obesity. Few studies, however, have explored some of the lifestyle behaviors (i.e., grocery shopping and cooking methods) thought to contribute to postoperative weight maintenance. To date, the child feeding practices of women who have undergone bariatric surgery have not been explored. The study setting was a university in the United States. METHODS: A total of 41 women awaiting bariatric surgery were assessed preoperatively; an additional 23 women who had undergone bariatric surgery (6-24 mo previously) were also assessed. The participants had to be responsible for feeding a child (age range 2-16 yr) in their home. Self-report measures assessed demographics, maternal child feeding practices, eating behaviors, and available household foods. Bivariate correlations were used to investigate the relationships among the measures. Independent sample t tests assessed group differences, and 1-way analysis of variance and concepts of linear progression and regression were used to determine whether the findings remained statistically significant after controlling for demographic variables. RESULTS: Women who had undergone surgery, compared with those awaiting surgery, reported more frequent modeling of healthy eating for their child (P = .009), significantly greater levels of cognitive restraint (P = .001), and lower levels of disinhibition (P = .019). Some between-group differences were found in grocery shopping frequency (P = .093) and in select foods available in the home (P = .101 to P = .151), which approached statistical significance. CONCLUSION: Mothers who had undergone bariatric surgery demonstrated healthy eating for their child and were engaged in healthier eating behaviors themselves compared with women awaiting surgery. Intervening with mothers who are undergoing bariatric surgery could present a unique opportunity for modifying the home food environment and promoting healthy eating among other family members, especially those children at risk of extreme obesity.

Social problem solving and depression in couples coping with cancer.

OBJECTIVE: When one person in a couple has cancer, both members may experience depressive symptoms and may react as an emotional system. However, the variables that influence this depressive system have not been identified. This study examined whether social problem solving, an important moderator of individual cancer-related depression, is related to depression in the couple system. METHODS: Sixty-three couples with one partner diagnosed with cancer completed self-report questionnaires regarding depressive symptoms, social problem solving, and relationship satisfaction. RESULTS: Multiple regression correlations supported the hypothesis that depression occurs in an emotional system (patient depression predicted partner depression and partner depression predicted patient depression). When examining how partner social problem solving impacts transmission from patient to partner, hierarchical multiple regression demonstrated that one social problem-solving component (positive problem orientation) eliminated the prediction of partner depression by patient depression. No other component of partner social problem solving eliminated the prediction of partner depression by patient depression. Partner social problem solving had no effect on whether partner depression predicted patient depression. CONCLUSIONS: Partners with more positive beliefs about solving problems were less likely to experience depression together with the patients. Further investigation into the role of social problem solving in the interpersonal depression system is warranted.

Discovery of a novel series of selective HCN1 blockers.

The discovery of a series of novel, potent, and selective blockers of the cyclic nucleotide-modulated channel HCN1 is disclosed. Here we report an SAR study around a series of selective blockers of the HCN1 channel. Utilization of a high-throughput VIPR assay led to the identification of a novel series of 2,2-disubstituted indane derivatives, which had moderate selectivity and potency at HCN1. Optimization of this hit led to the identification of the potent, 1,1-disubstituted cyclohexane HCN1 blocker, 2-ethoxy-N-((1-(4-isopropylpiperazin-1-yl)cyclohexyl)methyl)benzamide. The work leading to the discovery of this compound is described herein.

Practical and scalable synthesis of a selective CCK1 receptor antagonist.

We describe a practical and scalable route to compound (Z)-1, a selective CCK1 receptor antagonist. Notable features of this concise route are (1) a regioselective construction of the pyrazole core through the reaction of an aryl hydrazine and an elaborated acetylenic ketone, (2) a Tf2O/pyridine mediated Z-selective dehydration of an α-hydroxyester, and (3) a stereoselective hydrolysis. The sequence is high-yielding and amenable for large-scale synthesis.

Indole- and benzothiophene-based histamine H3 antagonists.

Previous research on histamine H(3) antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. Recent investigation of the replacement of the central phenyl core with heteroaromatic fragments resulted in the preparation of novel 3,5-, 3,6- and 3,7-substituted indole and 3,5-substituted benzothiophene analogs that demonstrate good to excellent hH(3) affinities. Select analogs were profiled in a rat pharmacokinetic model.

Feasibility study of a retinal prosthesis: spatial vision with a 16-electrode implant.

OBJECTIVE: To demonstrate that an epiretinal prosthesis can produce patterned visual perception in patients blinded by photoreceptor degeneration who have no other treatment options. METHODS: A totally blind subject with retinitis pigmentosa had a 16-electrode epiretinal prosthesis implanted. The implant is controlled wirelessly by an external computer or a head-mounted video camera. Spatial vision was assessed by measuring the subject's response to direct stimulation of patterns and by comparing the ability of the subject to identify the orientation of gratings with the system on and off. RESULTS: In response to stimulation of 2 orthogonal rows of electrodes, the subject drew 2 lines with a mean (SEM) angle of 87.4 degrees (1.8 degrees) between them. With the system on, the subject identified the orientation of the grating target up to a spatial resolution that matches the spacing between the adjacent electrodes. In contrast, with the system off, the subject could not detect or identify the target's orientation. CONCLUSION: Synchronized stimulation of different retinal locations with an epiretinal prosthesis implanted long-term can produce spatial vision with an acuity level determined by the distance between the electrodes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00279500.

SAR studies of 1,5-diarylpyrazole-based CCK1 receptor antagonists.

A high throughput screening campaign revealed compound 1 as a potent antagonist of the human CCK(1) receptor. Here, we report the syntheses and SAR studies of 1,5-diarylpyrazole analogs with various structural modifications of the alkane side chain of the molecule. The difference in affinity between the two enantiomers for the CCK(1) receptor and the flexible nature of the linker led to the design of constrained analogs with increased potency.

3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate (JNJ-17156516), a novel, potent, and selective cholecystokinin 1 receptor antagonist: in vitro and in vivo pharmacological comparison with dexloxiglumide.

3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate (JNJ-17156516) is a novel, potent, and selective cholecystokinin (CCK)1-receptor antagonist. In this study, the pharmacology of JNJ-17156516 was investigated both in vitro and in vivo, and the pharmacokinetic profile was evaluated in rats. JNJ-17156516 expressed high-affinity at the cloned human (pK(I) = 7.96 +/- 0.11), rat (pK(I) = 8.02 +/- 0.11), and canine (pK(I) = 7.98 +/- 0.04) CCK1 receptors, and it was also highly selective for the CCK1 receptor compared with the CCK2 receptor across the same species ( approximately 160-, approximately 230-, and approximately 75-fold, respectively). The high affinity of JNJ-17156516 at CCK1 receptors in vitro was confirmed in radioligand binding studies on fresh human gallbladder tissue (pK(I) = 8.22 +/- 0.05). In a functional in vitro assay of guinea pig gallbladder contraction, JNJ-17156516 behaved as a competitive antagonist, with a pK(B) value of 8.00 +/- 0.07. In vivo, JNJ-17156516 produced a parallel, rightward shift in the CCK-8S-evoked contraction of the guinea pig gallbladder. The dose required to shift the CCK-8S dose-response curve was 240 nmol kg(-1) i.v. In the anesthetized rat, JNJ-17156516 produced a dose-related decrease in the number of duodenal contractions evoked by infusion of CCK-8S, with an ED(50) = 484 nmol kg(-1). Pharmacokinetic analysis of JNJ-17156516 in rats, revealed that JNJ-17156516 had a half-life of 3.0 +/- 0.5 h and a very high bioavailability (108 +/- 10%) in this species. Overall, we have demonstrated that JNJ-17156516 is a high-affinity selective human CCK1 receptor antagonist with good pharmacokinetic properties in rats.

Novel non-benzimidazole chk2 kinase inhibitors.

In a recent paper, [Arienti, K. L.; Brunmark, A.; Axe, F. U.; McClure, K. M.; Lee, A.; Blevitt, J.; Neff, D. K.; Huang, L.; Crawford, S.; Chennagiri, R. P.; Karlsson, L.; Brietenbucher, J. G. J. Med. Chem.2005, 48, 1873], we described the discovery of a class of benzimidazole chk2 kinase inhibitors, exemplified by compound 1, which had radio-protective effects in human T-cells subjected to ionizing radiation. Here, a series of non-benzimidazole analogs intended to define the scope of the SAR about this new series of inhibitor, and allow for refinement of the binding model of these compounds to the chk2 kinase is described.

Pyrazole CCK(1) receptor antagonists. Part 2: SAR studies by solid-phase library synthesis and determination of Free-Wilson additivity.

High-throughput screening revealed compound 1 as a potent antagonist of the CCK(1) receptor. Here, we disclose the synthesis of combinatorial libraries by solid-phase synthesis on Kenner 'safety catch' resin. Additive QSAR models were used to determine a lack of consistent additive SAR within the matrix.

Pyrazole CCK(1) receptor antagonists. Part 1: Solution-phase library synthesis and determination of Free-Wilson additivity.

High throughput screening revealed compound 1 as a potent antagonist of the CCK(1) receptor. Evaluation of the CCK(1) SAR in a series of these diarylpyrazole antagonists was conducted in a matrix synthesis format revealing additive (Free-Wilson) and non-additive SAR. This use of additive QSAR modeling in conjunction with combinatorial libraries represents a unique approach to the evaluation of SAR interactions between the variables of any combinatorial matrix.