Identification of Cyanamide-Based Janus Kinase 3 (JAK3) Covalent Inhibitors.

Ongoing interest in the discovery of selective JAK3 inhibitors led us to design novel covalent inhibitors that engage the JAK3 residue Cys909 by cyanamide, a structurally and mechanistically differentiated electrophile from other cysteine reacting groups previously incorporated in JAK3 covalent inhibitors. Through crystallography, kinetic, and computational studies, interaction of cyanamide 12 with Cys909 was optimized leading to potent and selective JAK3 inhibitors as exemplified by 32. In relevant cell-based assays and in agreement with previous results from this group, 32 demonstrated that selective inhibition of JAK3 is sufficient to drive JAK1/JAK3-mediated cellular responses. The contribution from extrahepatic processes to the clearance of cyanamide-based covalent inhibitors was also characterized using metabolic and pharmacokinetic data for 12. This work also gave key insights into a productive approach to decrease glutathione/glutathione S-transferase-mediated clearance, a challenge typically encountered during the discovery of covalent kinase inhibitors.

Discovery and Lead Optimization of Atropisomer D1 Agonists with Reduced Desensitization.

The discovery of D1 subtype-selective agonists with drug-like properties has been an enduring challenge for the greater part of 40 years. All known D1-selective agonists are catecholamines that bring about receptor desensitization and undergo rapid metabolism, thus limiting their utility as a therapeutic for chronic illness such as schizophrenia and Parkinson's disease. Our high-throughput screening efforts on D1 yielded a single non-catecholamine hit PF-4211 (6) that was developed into a series of potent D1 receptor agonist leads with high oral bioavailability and CNS penetration. An important structural feature of this series is the locked biaryl ring system resulting in atropisomerism. Disclosed herein is a summary of our hit-to-lead efforts on this series of D1 activators culminating in the discovery of atropisomer 31 (PF-06256142), a potent and selective orthosteric agonist of the D1 receptor that has reduced receptor desensitization relative to dopamine and other catechol-containing agonists.

Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans.

Significant work has been dedicated to the discovery of JAK kinase inhibitors resulting in several compounds entering clinical development and two FDA approved NMEs. However, despite significant effort during the past 2 decades, identification of highly selective JAK3 inhibitors has eluded the scientific community. A significant effort within our research organization has resulted in the identification of the first orally active JAK3 specific inhibitor, which achieves JAK isoform specificity through covalent interaction with a unique JAK3 residue Cys-909. The relatively rapid resynthesis rate of the JAK3 enzyme presented a unique challenge in the design of covalent inhibitors with appropriate pharmacodynamics properties coupled with limited unwanted off-target reactivity. This effort resulted in the identification of 11 (PF-06651600), a potent and low clearance compound with demonstrated in vivo efficacy. The favorable efficacy and safety profile of this JAK3-specific inhibitor 11 led to its evaluation in several human clinical studies.

Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition.

PF-06651600, a newly discovered potent JAK3-selective inhibitor, is highly efficacious at inhibiting γc cytokine signaling, which is dependent on both JAK1 and JAK3. PF-06651600 allowed the comparison of JAK3-selective inhibition to pan-JAK or JAK1-selective inhibition, in relevant immune cells to a level that could not be achieved previously without such potency and selectivity. In vitro, PF-06651600 inhibits Th1 and Th17 cell differentiation and function, and in vivo it reduces disease pathology in rat adjuvant-induced arthritis as well as in mouse experimental autoimmune encephalomyelitis models. Importantly, by sparing JAK1 function, PF-06651600 selectively targets γc cytokine pathways while preserving JAK1-dependent anti-inflammatory signaling such as the IL-10 suppressive functions following LPS treatment in macrophages and the suppression of TNFα and IL-1ß production in IL-27-primed macrophages. Thus, JAK3-selective inhibition differentiates from pan-JAK or JAK1 inhibition in various immune cellular responses, which could potentially translate to advantageous clinical outcomes in inflammatory and autoimmune diseases.

Discovery of selective N-[3-(1-methyl-piperidine-4-carbonyl)-phenyl]-benzamide-based 5-HT1 F receptor agonists: Evolution from bicyclic to monocyclic cores.

Preclinical experiments and clinical observations suggest the potential effectiveness of selective 5-HT1F receptor agonists in migraine. Identifying compounds with enhanced selectivity is crucial to assess its therapeutic value. Replacement of the indole nucleus in 2 (LY334370) with a monocyclic phenyl ketone moiety generated potent and more selective 5-HT1F receptor agonists. Focused SAR studies around this central phenyl ring demonstrated that the electrostatic and steric interactions of the substituent with both the amide CONH group and the ketone CO group play pivotal roles in affecting the adopted conformation and thus the 5-HT1F receptor selectivity. Computational studies confirmed the observed results and provide a useful tool in the understanding of the conformational requirements for 5-HT1F receptor agonist activity and selectivity. Through this effort, the 2-F-phenyl and N-2-pyridyl series were also identified as potent and selective 5-HT1F receptor agonists.

Long-Term Refugee Health: Health Behaviors and Outcomes of Cambodian Refugee and Immigrant Women.

Refugees in the United States have high rates of chronic disease. Both long-term effects of the refugee experience and adjustment to the U.S. health environment may contribute. While there is significant research on health outcomes of newly resettled refugees and long-term mental health experiences of established refugees, there is currently little information about how the combined effects of the refugee experience and the U.S. health environment are related to health practices of refugees in the years and decades after resettlement. We examined cross-sectional survey data for Cambodian refugee and immigrant women 35 to 60 years old (n = 160) from an established refugee community in Lowell, Massachusetts, to examine the potential contributors to health behaviors and outcomes among refugees and immigrants postresettlement. In our representative sample, we found that smoking and betel nut use were very low (4% each). Fewer than 50% of respondents walked for at least 10 minutes on 2 or more days/week. Using World Health Organization standards for overweight/obese for Asians, 73% of respondents were overweight/obese and 56% were obese, indicating increased risk of chronic disease. Depression was also high in this sample (41%). In multivariate models, higher acculturation and age were associated with walking more often; lower education and higher acculturation were related to higher weight; and being divorced/separated or widowed and being older were related to higher risk of depression. The interrelated complex of characteristics, health behaviors, and health outcomes of refugees merits a multifaceted approach to health education and health promotion for long-term refugee health.

Health behaviors among Cambodian adults in Lowell, Massachusetts.

Physical activity, maintaining healthy weight, eating fruits and vegetables, and non-smoking are health behaviors that reduce risk for a variety of poor health outcomes. This analysis reports frequencies and socio-demographic correlates of these behaviors among 381 Cambodians aged 25 and older surveyed in Lowell, MA. The majority reported some physical activity (72 %), healthy weight (62 %), and not smoking (77 %). Only 28 % reported adequate fruit and vegetable consumption. Four multivariable models indicate that (1) physical activity was associated with higher income, lower levels of US education, reading English, and living in the US 11-19 years; (2) healthy weight with living in the US 20 or more years; (3) not smoking with being female and living in the US less than 11 years; and (4) adequate fruit and vegetable consumption with lower levels of US education and reading English. These results inform public health planning for Cambodians.

Long-term development of a "whole community" best practice model to address health disparities in the Cambodian refugee and immigrant community of Lowell, Massachusetts.

Cambodians in Lowell, Massachusetts, experience significant health disparities. Understanding the trauma they have experienced in Cambodia and as refugees has been the starting point for Lowell Community Health Center's whole community approach to developing community-based interventions. This approach places physical-psychosocial-spiritual needs at the center of focus and is attentive to individual and institutional barriers to care. Interventions are multilevel. The effect of the overall program comes from the results of each smaller program, the collaborations and coordination with the Cambodian community and community-based organizations, and the range and levels of services available through the health center.

Relationship between past food deprivation and current dietary practices and weight status among Cambodian refugee women in Lowell, MA.

OBJECTIVES: We investigated Cambodian refugee women's past food experiences and the relationship between those experiences and current food beliefs, dietary practices, and weight status. METHODS: Focus group participants (n = 11) described past food experiences and current health-related food beliefs and behaviors. We randomly selected survey participants (n = 133) from a comprehensive list of Cambodian households in Lowell, Massachusetts. We collected height, weight, 24-hour dietary recall, food beliefs, past food experience, and demographic information. We constructed a measure of past food deprivation from focus group and survey responses. We analyzed data with multivariate logistic and linear regression models. RESULTS: Participants experienced severe past food deprivation and insecurity. Those with higher past food-deprivation scores were more likely to currently report eating meat with fat (odds ratio [OR] = 1.14 for every point increase on the 9-to-27-point food-deprivation measure), and to be overweight or obese by Centers for Disease Control and Prevention (OR = 1.28) and World Health Organization (OR = 1.18) standards. CONCLUSIONS: Refugees who experienced extensive food deprivation or insecurity may be more likely to engage in unhealthful eating practices and to be overweight or obese than are those who experienced less-extreme food deprivation or insecurity.

Decreases in smoking prevalence in Asian communities served by the Racial and Ethnic Approaches to Community Health (REACH) project.

OBJECTIVES: We examined trends in smoking prevalence from 2002 through 2006 in 4 Asian communities served by the Racial and Ethnic Approaches to Community Health (REACH) intervention. METHODS: Annual survey data from 2002 through 2006 were gathered in 4 REACH Asian communities. Trends in the age-standardized prevalence of current smoking for men in 2 Vietnamese communities, 1 Cambodian community, and 1 Asian American/Pacific Islander (API) community were examined and compared with nationwide US and state-specific data from the Behavioral Risk Factor Surveillance System. RESULTS: Prevalence of current smoking decreased dramatically among men in REACH communities. The reduction rate was significantly greater than that observed in the general US or API male population, and it was greater than reduction rates observed in the states in which REACH communities were located. There was little change in the quit ratio of men at the state and national levels, but there was a significant increase in quit ratios in the REACH communities, indicating increases in the proportions of smokers who had quit smoking. CONCLUSIONS: Smoking prevalence decreased in Asian communities served by the REACH project, and these decreases were larger than nationwide decreases in smoking prevalence observed for the same period. However, disparities in smoking prevalence remain a concern among Cambodian men and non-English-speaking Vietnamese men; these subgroups continue to smoke at a higher rate than do men nationwide.

Hepatitis B testing and vaccination among Vietnamese- and Cambodian-Americans.

We determined hepatitis B virus (HBV) testing and vaccination levels and factors associated with testing and vaccination among Vietnamese- and Cambodian-Americans. We also examined factors associated with healthcare professional (HCP)-patient discussions about HBV. We analyzed 2006 Racial and Ethnic Approaches to Community Health (REACH) 2010 Risk Factor Survey data from four US communities. We used logistic regression to identify variables associated with HBV vaccination, testing, and HCP-patient discussions about HBV. Of the 2,049 Vietnamese- and Cambodian-American respondents, 60% reported being tested for HBV, 35% reported being vaccinated against hepatitis B, and 36% indicated that they had discussed HBV with a HCP. Cambodian-Americans were less likely than Vietnamese-Americans to have been tested for HBV, while respondents with at least a high school diploma were more likely to have been tested for HBV. Respondents born in the US, younger individuals, and respondents with at least some college education were more likely to have been vaccinated against hepatitis B. HBV testing and vaccination remain suboptimal among members of these populations. Culturally sensitive efforts that target Vietnamese- and Cambodian-Americans for HBV testing and vaccination are needed to identify chronic carriers of HBV, prevent new infections, and provide appropriate medical management. HCPs that serve these populations should be encouraged to discuss HBV with their patients.

Building on the strengths of a Cambodian refugee community through community-based outreach.

Literature and practice are limited on strategies to reach elder Southeast Asian refugees by using their strengths and resilience. This article presents the Centers for Disease Control and Prevention-funded Cambodian Community Health 2010 Program in Lowell, Massachusetts, as a case example and provides refugee history, project background, community survey results about strengths and risks, literature on strengths-based approaches, outreach activities, and evaluation. The focus is elimination of health disparities in cardiovascular disease and diabetes. "Community conversations" and a daylong forum with community leaders were used to develop plans for outreach. A Cambodian Elders Council provided information and guidance used to refine the program. Key findings highlight involving elders in organizing events, avoiding reliance on literacy, integrating health promotion with socialization, using ties with Buddhist temples, developing transportation alternatives, and utilizing local Khmer-language media. Implications include applicability to other refugee communities with low literacy, high levels of trauma, limited English, and strong religious involvement.

Indanylacetic acids as PPAR-delta activator insulin sensitizers.

A series of indane acetic acid derivatives were prepared which show a spectrum of activity as insulin sensitizers and PPAR-alpha and PPAR-delta ligands. In vivo data are presented for insulin sensitizers with selectivity for PPAR-delta over PPAR-alpha.

PDE-10A inhibitors as insulin secretagogues.

Modulation of cAMP levels has been linked to insulin secretion in preclinical animal models and in humans. The high expression of PDE-10A in pancreatic islets suggested that inhibition of this enzyme may provide the necessary modulation to elicit increased insulin secretion. Using an HTS approach, we have identified quinoline-based PDE-10A inhibitors as insulin secretagogues in vitro. Optimized compounds were evaluated in vivo where improvements in glucose tolerance and increases in insulin secretion were measured.

Indanylacetic acid derivatives carrying aryl-pyridyl and aryl-pyrimidinyl tail groups--new classes of PPAR gamma/delta and PPAR alpha/gamma/delta agonists.

Modulation of PPAR activities represents an attractive approach for the treatment of diabetes with associated cardiovascular complications. The indanylacetic acid structural motif has proven useful in the generation of potent and tunable PPAR ligands. Modification of the substituents on the linker and the heterocycle tail group allowed for the modulation of the selectivity at the different receptor subtypes. Compound 33 was evaluated in vivo, where it displayed the desired reduction of glucose levels and increase in HDL levels in various animal models.

Self-reported health among Cambodians in Lowell, Massachusetts.

National health data reported for Asians in the aggregate present a picture of good health, but significant health disparities exist between Southeast Asian refugees, and Cambodians in particular, and the overall population of the U.S. To effectively address health disparities, ethnically specific data is needed. Data from a community survey of 381 Cambodian adults 25 years of age and older are presented. Overall, 44% of respondents reported fair or poor health. Using multivariate logistic regression, we examined the relationships between self-rated health and demographics, timing of immigration, language use and literacy, and access to health care. In our final model those most likely to report fair or poor health were female, older, unable to work due to disability, to have spent a smaller proportion of their life in the U.S., and to have wanted to see a doctor in the past year, but not been able to.

Design, synthesis and evaluation of bicyclic benzamides as novel 5-HT1F receptor agonists.

Several fused bicyclic systems have been investigated to serve as the core structure of potent and selective 5-HT1F receptor agonists. Replacement of the indole nucleus in 2 with indazole and 'inverted' indazole provided more potent and selective 5-HT1F receptor ligands. Indoline and 1,2-benzisoxazole systems also provided potent 5-HT1F receptor agonists, and the 5-HT1A receptor selectivity of the indoline- and 1,2-benzisoxazole-based 5-HT1F receptor agonists could be improved with modification of the benzoyl moiety of the benzamides. Through these studies, we found that the inherent geometries of the templates, not the nature of hybridization of the linking atom, were important for the 5-HT1F receptor recognition.

Oxidative C-C bond-forming reaction of electron-rich alkylbenzyl ether with trimethylvinyloxysilane.

Treatment of an electron-rich benzyl ether with DDQ at ambient temperature followed by addition of a silyl enol ether undergoes a C-C bond-forming reaction to afford 3-alkoxy-3-phenyl-propionyl compound. This is a general reaction and works well with a variety of silyl enol ethers to give carbonyl products in yields ranging from 10 to 85%.

Tertiary pentyl groups enhance salen titanium catalyst for highly enantioselective trimethylsilylcyanation of aldehydes.

tert-Pentyl groups are recognized to be highly effective steric groups that can enhance enantioselectivity of salen titanium complexes when they are used in asymmetrical cyanation of aromatic aldehydes. High ee (92-97%) has been obtained with several aldehyde substrates. Compared to its tert-butyl analogue, the tert-pentyl group has been found to improve enantioselectivity and in some cases quite dramatically.