Toledo-Sherman, Leticia; Breccia, Perla; Cachope, Roger; Bate, Jennifer R.; Angulo-Herrera, Ivan; Wishart, Grant; Matthews, Kim L.; Martin, Sarah L.; Cox, Helen C.; McAllister, George; Penrose, Stephen D.; Vater, Huw; Esmieu, William; Van de Poel, Amanda; Van de Bospoort, Rhea; Strijbosch, Annelieke; Lamers, Marieke; Leonard, Philip; Jarvis, Rebecca E.; Blackaby, Wesley; Barnes, Karen; Eznarriaga, Maria; Dowler, Simon; Smith, Graham D.; Fischer, David F.; Lazari, Ovadia; Yates, Dawn; Rose, Mark; Jang, Sung-Wook; Munoz-Sanjuan, Ignacio; Dominguez, Celia published the artcile< Optimization of Potent and Selective Ataxia Telangiectasia-Mutated Inhibitors Suitable for a Proof-of-Concept Study in Huntington's Disease Models>, Synthetic Route of 16426-64-5, the main research area is ATM inhibitor Huntington’s disease mHTT PK PD brain penetrant.
Genetic and pharmacol. evidence indicates that the reduction of ataxia telangiectasia-mutated (ATM) kinase activity can ameliorate mutant huntingtin (mHTT) toxicity in cellular and animal models of Huntington’s disease (HD), suggesting that selective inhibition of ATM could provide a novel clin. intervention to treat HD. Here, we describe the development and characterization of ATM inhibitor mols. to enable in vivo proof-of-concept studies in HD animal models. Starting from previously reported ATM inhibitors, we aimed with few modifications to increase brain exposure by decreasing P-glycoprotein liability while maintaining potency and selectivity. Here, we report brain-penetrant ATM inhibitors that have robust pharmacodynamic (PD) effects consistent with ATM kinase inhibition in the mouse brain and an understandable pharmacokinetic/PD (PK/PD) relationship. Compound 17 engages ATM kinase and shows robust dose-dependent inhibition of X-ray irradiation-induced KAP1 phosphorylation in the mouse brain. Furthermore, compound 17 protects against mHTT (Q73)-induced cytotoxicity in a cortical-striatal cell model of HD.
Journal of Medicinal Chemistry published new progress about Crystal structure (X-ray structure of 33 bound to the mutant Vps34 construct). 16426-64-5 belongs to class bromides-buliding-blocks, and the molecular formula is C7H4BrNO4, Synthetic Route of 16426-64-5.
Referemce:
Bromide – Wikipedia,
bromide – Wiktionary