Application In Synthesis of Azetidin-3-ol hydrochlorideIn 2017 ,《Design, Synthesis, and Structure-Activity Relationship of Tetrahydropyrido[4,3-d]pyrimidine Derivatives as Potent Smoothened Antagonists with in Vivo Activity》 was published in ACS Chemical Neuroscience. The article was written by Lu, Wenfeng; Liu, Yongqiang; Ma, Haikuo; Zheng, Jiyue; Tian, Sheng; Sun, Zhijian; Luo, Lusong; Li, Jiajun; Zhang, Hongjian; Yang, Zeng-Jie; Zhang, Xiaohu. The article contains the following contents:
Abstract: Medulloblastoma is one of the most prevalent brain tumors in children. Aberrant hedgehog (Hh) pathway signaling is thought to be involved in the initiation and development of medulloblastoma. Vismodegib, the first FDA-approved cancer therapy based on inhibition of aberrant hedgehog signaling, targets smoothened (Smo), a G-protein coupled receptor (GPCR) central to the Hh pathway. Although vismodegib exhibits promising therapeutic efficacy in tumor treatment, concerns have been raised from its nonlinear pharmacokinetic (PK) profiles at high doses partly due to low aqueous solubility Many patients experience adverse events such as muscle spasms and weight loss. In addition, drug resistance often arises among tumor cells during treatment with vismodegib. There is clearly an urgent need to explore novel Smo antagonists with improved potency and efficacy. Through a scaffold hopping strategy, the authors have identified a series of novel tetrahydropyrido[4,3-d]pyrimidine derivatives, which exhibited effective inhibition of Hh signaling. Among them, compound I is three times more potent than vismodegib in the NIH3T3-GRE-Luc reporter gene assay. Compound I has lower m.p. and much greater solubility compared with vismodegib, resulting in linear PK profiles when dosed orally at 10, 30, and 100 mg/kg in rats. Furthermore, compound I showed excellent PK profiles with a 72% oral bioavailability in beagle dogs. Compound I demonstrated overall favorable in vitro safety profiles with respect to CYP isoform and hERG inhibition. Finally, compound I led to significant regression of s.c. tumor generated by primary Ptch1-deficient medulloblastoma cells in SCID mouse. In conclusion, tetrahydropyrido[4,3-d]pyrimidine derivatives represent a novel set of Smo inhibitors that could potentially be utilized to treat medulloblastoma and other Hh pathway related malignancies. The results came from multiple reactions, including the reaction of Azetidin-3-ol hydrochloride(cas: 18621-18-6Application In Synthesis of Azetidin-3-ol hydrochloride)
Azetidin-3-ol hydrochloride(cas:18621-18-6) is one of azetidine.Azetidines (azacyclobutanes) constitute a well-known class of heterocyclic compounds. Azetidine scaffold has been discovered in several natural products.Application In Synthesis of Azetidin-3-ol hydrochloride Several pharmacologically important synthetic compounds also contain azetidine ring. Because of inherent ring strain, the synthesis of azetidines is a challenging endeavor.
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