159451-66-8Relevant articles and documents
Synthesis of [N-methyl- 11C]-3-[(6-dimethylamino)pyridin-3-yl]-2,5-dimethyl-N, N-dipropylpyrazolo[1,5-a]pyrimidine-7-amine: A potential PET ligand for in vivo imaging of CRF1 receptors
Kumar, J.S. Dileep,Majo, Vattoly J.,Prabhakaran, Jaya,Simpson, Norman R.,Van Heertum, Ronald L.,John Mann
, p. 1055 - 1065 (2003)
A convenient synthesis of [N-methyl- 11C]-3-[(6-dimethylamino)pyridin-3-yl]-2,5-dimethyl-N, N-dipropylpyrazolo[1,5-a]pyrimidine-7-amine (R121920), a highly selective CRF1 antagonist has been developed as a potential PET ligand. 3-[(6-methylamino)pyridin-3-yl]-2,5-dimethyl-N,N-dipropylpyrazolo [1,5-a]pyrimidine-7-amine (7), the precursor for radiolabelling was synthesized through a novel palladium catalyzed Suzuki coupling of aryl bromide 5 with heteroaryl boronate ester 4. The requisite boronate ester 4 was synthesized in four steps from 2-amino-4-bromopyridine in 50% overall yield. Although the synthesis of cold R121920 proceeded in 93% yield by sodium hexamethyl-disilazide (NaHMDS) mediated N-methylation of the desmethylamine 7 at -78°C, the attempted radiosynthesis under various conditions using conventional bases were not successful. However, the radiolabeling of [ 11C]R121920 was successfully carried out with [11C]MeOTf in acetone at -20°C in the absence of added basic reagents. The radiotracer was purified by RP-HPLC followed by RP-solid phase extraction. The yield of the reaction was 5% (at EOB) and the specific activity was > 1000 Ci/mmol (at EOB) with a radiochemical purity > 99%. Copyright
MRGPRX2 ANTAGONISTS AND USES THEREOF
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Paragraph 00282-00283, (2021/05/15)
The present disclosure is directed to use of MrgprX2 antagonists in the treatment of inflammatory disorders, e.g., inflammatory disorders of the skin. This invention is also directed to pharmaceutical compositions comprising a MrgprX2 antagonist and a pharmaceutically or orally acceptable carrier for administration.
Discovery of a First-in-Class Gut-Restricted RET Kinase Inhibitor as a Clinical Candidate for the Treatment of IBS
Schenck Eidam, Hilary,Russell, John,Raha, Kaushik,Demartino, Michael,Qin, Donghui,Guan, Huiping Amy,Zhang, Zhiliu,Zhen, Gong,Yu, Haiyu,Wu, Chengde,Pan, Yan,Joberty, Gerard,Zinn, Nico,Laquerre, Sylvie,Robinson, Sharon,White, Angela,Giddings, Amanda,Mohammadi, Ehsan,Greenwood-Van Meerveld, Beverly,Oliff, Allen,Kumar, Sanjay,Cheung, Mui
supporting information, p. 623 - 628 (2018/07/25)
Abdominal pain and abnormal bowel habits represent major symptoms for irritable bowel syndrome (IBS) patients that are not adequately managed. Although the etiology of IBS is not completely understood, many of the functions of the gastrointestinal (GI) tract are regulated by the enteric nervous system (ENS). Inflammation or stress-induced expression of growth factors or cytokines may lead to hyperinnervation of visceral afferent neurons in GI tract and contribute to the pathophysiology of IBS. Rearranged during transfection (RET) is a neuronal growth factor receptor tyrosine kinase critical for the development of the ENS as exemplified by Hirschsprung patients who carry RET loss-of-function mutations and lack normal colonic innervation leading to colonic obstruction. Similarly, RET signaling in the adult ENS maintains neuronal function by contributing to synaptic formation, signal transmission, and neuronal plasticity. Inhibition of RET in the ENS represents a novel therapeutic strategy for the normalization of neuronal function and the symptoms of IBS patients. Herein, we describe our screening effort and subsequent structure-activity relationships (SARs) in optimizing potency, selectivity, and mutagenicity of the series, which led to the discovery of a first-in-class, gut-restricted RET kinase inhibitor, 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (15, GSK3179106), as a clinical candidate for the treatment of IBS. GSK3179106 is a potent, selective, and gut-restricted pyridone hinge binder small molecule RET kinase inhibitor with a RET IC50 of 0.3 nM and is efficacious in vivo.