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After extensive synthetic efforts, we found that many structurally diverse bioisosteres could be generated via derivatizing the C-4 alkyl chain on the pyrazole ring of compound 3 (B/P = 1/33) with different electronegative groups. Especially when a sulfonamide or sulfamide moiety was added, resulting compounds exhibited not only potent CB1R activity but also a desired tPSA value over 90 Å(2), a threshold considered to possess a low probability to cross BBB, leading to the identification of compound 4 (B/P = 1/64) as a peripherally restricted CB1R antagonist. Apart from its significant weight-loss efficacy in DIO mice, compound 4 also displays 163 clean off-target profiles and is currently under development for treating obesity and the related metabolic syndrome.

BACKGROUND: Based on the high prevalence of people with problems in the wrist and hand simultaneously, it is of its importance to clarify whether hand joints exert extra motion to compensate for wrist motion while immobilized. OBJECTIVE: This study aimed to measure the compensatory movement of the thumb and index finger when people perform daily activities with an immobilized wrist. METHODS: Thirty healthy volunteers were recruited in this study. A wrist splint, the Jebsen-Taylor Hand Function Test, and the OptoTrak Certus motion tracking system were used. Seven inter-digit mean joint angles of the index finger and thumb were calculated. Paired sample t-test was used. RESULTS: (1) The compensatory motions were noted in the Metacarpophalangeal and Carpometacarpal joints of the thumb, and the proximal interphalangeal joints of the index finger; (2) The manifestation of compensatory motion was related to type of activity performed except when picking up light and heavy cans. CONCLUSIONS: The compensatory motions appeared while the wrist was immobilized and were found to be disadvantageous to the progression of disease. In the future, studies need to be done to understand how to select products with correct ergonomic design to enable people to reap greater benefits from wearing wrist splints.

Our study suggests that PSTPIP2 could play a role in innate immunity and development of autoinflammatory bone disorders, and may be associated with the pathogenesis of human SAPHO syndrome.