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.

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.

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.

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.

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%.