SAR of carbon-linked, 2-substituted purines: synthesis and characterization of AP23451 as a novel bone-targeted inhibitor of Src tyrosine kinase with in vivo anti-resorptive activity.

Targeted disruption of the pp60(src) (Src) gene has implicated this tyrosine kinase in osteoclast-mediated bone resorption and as a therapeutic target for the treatment of osteoporosis and other bone-related diseases. Here, we describe structure activity relationships of a novel series of carbon-linked, 2-substituted purines that led to the identification of AP23451 as a potent inhibitor of Src tyrosine kinase with antiresorptive activity in vivo. AP23451 features the use of an arylphosphinylmethylphosphinic acid moiety which confers bone-targeting properties to the molecule, thereby increasing local concentrations of the inhibitor to actively resorbing osteoclasts at the bone interface. AP23451 exhibited an IC50 = 68 nm against Src kinase; an X-ray crystal structure of the molecule complexed with Src detailed the molecular interactions responsible for its Src inhibition. In vivo, AP23451 demonstrated a dose-dependent decrease in PTH-induced hypercalcemia. Moreover, AP23517, a structurally and biochemically similar molecule with comparable activity (IC50 = 73 nm) except devoid of the bone-targeting element, demonstrated significantly reduced in vivo efficacy, suggesting that Src activity was necessary but not sufficient for in vivo activity in this series of compounds.

Visual acuity testability in African-American and Hispanic children: the multi-ethnic pediatric eye disease study.

PURPOSE: To compare the age- and gender-specific testability rates for the Amblyopia Treatment Study (ATS) HOTV visual acuity testing protocol using the electronic visual acuity (EVA) tester in African-American and Hispanic preschool children. DESIGN: Population-based, cross-sectional study. METHODS: Measurement of presenting monocular distance visual acuity using the ATS HOTV protocol was attempted in all African-American and Hispanic children aged 30 to 72 months from the population-based Multi-Ethnic Pediatric Eye Disease Study (MEPEDS). Children able to be tested monocularly in both eyes were considered able. Age-, gender-, and ethnicity-specific testability rates were calculated. Comparisons of testability among different groups were performed using Chi-square analyses and the Cochran trend test. RESULTS: Testing was attempted on 3,126 children (1,471 African-American, 1,655 Hispanic; 50% female). Overall, 84% (83% African-American, 85% Hispanic; 86% female, 82% male) were testable. Older children were more likely to complete testing successfully than younger children (P < .0001). Age-specific testability in children 30 to 36 months of age, 37 to 48 months of age, 49 to 60 months of age, and 61 to 72 months of age was 39%, 84%, 98%, and 100%, respectively. After stratifying by age, there were no ethnicity-related differences in children testable (P = .12). Girls (86%) were slightly more likely to be testable than boys (82%; P > .003). CONCLUSIONS: Monocular threshold visual acuity testing using the ATS HOTV protocol on the EVA tester (Jaeb Center for Health Research, Tampa, Florida, USA) can be completed by most African-American and Hispanic preschool children, particularly those older than 36 months of age. This protocol therefore may be used in minority preschool children as an integral part of the diagnosis and management of amblyopia and other forms of visual impairment.