We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent I current blocker with selectivity versus hERG, Na and Ca channels, and an acceptable preclinical PK profile. Upon further characterization in vivo, compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2' position for a series of close analogues by employing hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide (25) was identified as the lead compound in this series. Compound 25 showed robust effects in rabbit and canine pharmacodynamic models and an acceptable cross-species pharmacokinetic profile and was advanced as the clinical candidate. Further optimization of 25 to mitigate pH-dependent absorption resulted in identification of the corresponding phosphoramide prodrug (29) with an improved solubility and pharmacokinetic profile.

G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp/sp character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitro. In vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.

With a view to explaining the effect of m-cresol on the kinetics of dye uptake by wool and other proteins, a study has been made of the interaction of Biebrich Scarlet (C.I. Acid Red 66) with achymotrypsin in the presence and absence of m-cresol. It has been found that a 1 : 1 dye-protein complex is formed in the absence of m-cresol and that m-cresol displaces the dye from the complex through allosteric competition.

BackgroundTo assess reduction in heavy menstrual bleeding and dysmenorrhea following MRI guided Focused Ultrasound Surgery (MRgFUS) of focal and diffuse adenomyosis up to 12 months post-treatment a retrospective cohort study was done at a tertiary care academic medical center for obstetrics, gynecology and infertility.MethodsMRgFUS for adenomyosis uterus was done for thirty-seven patients presenting with symptoms of heavy menstrual bleeding and dysmenorrhea with MRI-suspected adenomyosis. The main outcome measure, was reduction in heavy menstrual bleeding, dysmenorrhea and Symptom Severity Scoring (SSS) over a 3, 6 and 12 month period. Secondary outcome was evidence of fertility preservation post procedure. D’Agostino & Pearson omnibus normality test, one-way Ananova, Pearson’s correlation coefficient analysis was performed on the data. Statistical significances, p-value and r-value were determined.ResultsOut of 37 patients who were treated by MRgFUS, 26 had sufficient follow-up to be included in the analysis. SSS calculated at 3, 6 and 12 months was significantly over the baseline. Both heavy menstrual bleeding and dysmenorrhea, which were assessed separately, were found to significantly improve over time with a positive correlation between the two. No other intervention was required. ConclusionMRgFUS provides immediate and sustained relief for patients with focal and diffuse adenomyosis. Electronic supplementary materialThe online version of this article (doi:10.1186/s40738-016-0021-x) contains supplementary material, which is available to authorized users.

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