Design and synthesis of morpholine derivatives. SAR for dual serotonin & noradrenaline reuptake inhibition.

Single enantiomer (SS) and (RR) 2-[(phenoxy)(phenyl)methyl]morpholine derivatives 5, 8-23 are inhibitors of monoamine reuptake. Target compounds were prepared using an enantioselective synthesis employing a highly specific enzyme-catalysed resolution of racemic n-butyl 4-benzylmorpholine-2-carboxylate (26) as the key step. Structure-activity relationships established that serotonin and noradrenaline reuptake inhibition are functions of stereochemistry and aryl/aryloxy ring substitution. Consequently, selective SRI, selective NRI and dual SNRIs were all identified. One of these compounds, a potent and selective dual SNRI, (SS)-5a was selected as a candidate for further pre-clinical evaluation.

Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.

The Type 1 PI3Kinases comprise a family of enzymes, which primarily phosphorylate PIP2 to give the second messenger PIP3, a key player in many intracellular signaling processes [Science, 2002, 296, 1655; Trends Pharmacol. Sci.2003, 24, 366]. Of the four type 1 PI3Ks, the gamma-isoform, which is expressed almost exclusively in leukocytes [Curr. Biol., 1997, 7, R470], is of particular interest with respect to its role in inflammatory diseases such as rheumatoid arthritis (RA) and chronic obstructive pulmonary disease (COPD) [Mol. Med. Today, 2000, 6, 347]. Investigation of a series of 4,6-disubstituted-4H-benzo[1,4]oxazin-3-ones has led to the identification of single-digit nanomolar inhibitors of PI3Kgamma, several of which had good cell based activity and were shown to be active in vivo in an aspectic peritonitis model of inflammatory cell migration.

Occlusal perceptions of children seeking orthodontic treatment: impact of ethnicity and socioeconomic status.

INTRODUCTION: With the growth of orthodontic intervention at younger ages and increased interest in improving dentofacial appearance among the general public, it is important to assess whether demand for treatment is uniform across ethnic and socioeconomic groups. METHODS: This study compared 3 groups of children who varied by location, payment source, and ethnicity. The sample consisted of 150 children in the Bronx, NY, and 100 in Seattle, Wash, who were undergoing or anticipating orthodontic treatment in publicly funded dental clinics. Ethnic minorities comprised 69% and 92%, respectively, of these groups. The third group consisted of 84 children in Seattle, Anchorage (Alaska), and Chicago who had sought treatment by private practitioners; ethnic minorities comprised 22% of this group. Data were collected from children and parents or guardians by questionnaires. RESULTS: Desire for treatment was higher among children in the publicly funded clinics and among black children than whites or Asian Americans. Children in publicly funded clinics rated themselves as having worse occlusions as determined by anterior crowding, overbite, overjet, diastema, and open bite. Children in the Bronx clinic accepted a wider range of occlusion as attractive. Stage of treatment affected judgments of attractiveness. Vicarious experience with orthodontics through parents or siblings made children more tolerant of dentofacial disharmony, with more favorable ratings of malocclusion in this group than among children who had no family experience with orthodontics. Hispanic and mixed-ethnicity children rated themselves more negatively on all dimensions. CONCLUSIONS: These results suggest that both socioeconomic status and ethnicity play roles in children's desire for treatment, self-assessed need, and judgments of esthetics. A clinician's sensitivity to such differences can improve patient cooperation with treatment.