147804-30-6Relevant articles and documents
Synthesis and SAR of Imidazo[1,5-a[pyridine derivatives as 5-HT4 receptor partial agonists for the treatment of cognitive disorders associated with Alzheimer's disease
Nirogi, Ramakrishna,Mohammed, Abdul Rasheed,Shinde, Anil K.,Bogaraju, Narsimha,Gagginapalli, Shankar Reddy,Ravella, Srinivasa Rao,Kota, Laxman,Bhyrapuneni, Gopinadh,Muddana, Nageswara Rao,Benade, Vijay,Palacharla, Raghava Chowdary,Jayarajan, Pradeep,Subramanian, Ramkumar,Goyal, Vinod Kumar
, p. 289 - 301 (2015)
Alzheimer's disease (AD) is a neurodegenerative disease which has a higher prevalence and incidence in older people. The need for improved AD therapies is unmet. The 5-hydroxytryptamine4 receptor (5-HT4R) partial agonists may be of benefit for both the symptomatic and disease-modifying treatment of cognitive disorders associated with AD. Herein, we report the design, synthesis and SAR of imidazo[1,5-a] pyridine derivatives as 5-HT4R partial agonists. The focused SAR, optimization of ADME properties resulted the discovery of compound 5a as potent, selective, brain penetrant 5-HT4 partial agonist as a lead compound with good ADME properties and efficacy in both symptomatic and disease modifying animal models of cognition.
The synthesis of a 2-azabicyclo[3.1.0]hexane by rearrangement of a spirocyclic epoxide
Adamovskyi, Mykhailo I.,Artamonov, Oleksiy S.,Tymtsunik, Andriy V.,Grygorenko, Oleksandr O.
, p. 5970 - 5972 (2014)
An unusual rearrangement of a 1-oxa-6-azaspiro[2.5]octane derivative giving access to novel 5-substituted 2-azabicyclo[3.1.0]hexanes is described. The synthetic application of the reaction is demonstrated by the synthesis of N-Boc-2,3-methano-β-proline. The amino acid was prepared through a three-step synthesis from easily available reagents in an overall yield of 15%.
Design, synthesis, biological evaluation and structure-activity relationship study of quinazolin-4(3H)-one derivatives as novel USP7 inhibitors
Li, Peng,Liu, Ying,Yang, Hua,Liu, Hong-Min
, (2021/03/09)
Recent research has indicated that the abnormal expression of the deubiquitinase USP7 induces tumorigenesis via multiple cell pathways, and in particular, the p53-MDM2-USP7 pathway is well understood. USP7 is emerging as a promising target for cancer therapy. However, there are limited reports on USP7 inhibitors. Here we report design, synthesis and biological evaluation of novel quinazolin-4(3H)-one derivatives as potent USP7 inhibitors. Our results indicated that the compounds C9 and C19 exhibited the greatest potency against the USP7 catalytic domain, with IC50 values of 4.86 μM and 1.537 μM, respectively. Ub-AMC assays further confirmed IC50 values of 5.048 μM for C9 and 0.595 μM for C19. MTT assays indicated that gastric cancer MGC-803 cells were more sensitive to these compounds than BGC-823 cells. Flow cytometry analysis revealed that C9 restricted cancer cell growth at the G0/G1 and S phases and inhibited the proliferation and clone formation of MGC-803 cells. Further biochemical experiments indicated that C9 decreased the MDM2 protein level and increased the levels of the tumour suppressors p53 and p21 in a dose-dependent manner. Docking studies predicted that solvent exposure of the side chains of C9 and C19 would uniquely form hydrogen bonds with Met407 of USP7. Additionally, C9 exhibited a remarkable anticancer effect in a zebrafish gastric cancer MGC-803 cell model. Our results demonstrated that quinazolin-4(3H)-one derivatives were suitable as leads for the development of novel USP7 inhibitors and especially for anti-gastric cancer drugs.
IMINO SULFANONE INHIBITORS OF ENPP1
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Paragraph 0226, (2021/11/13)
The present disclosure relates generally to inhibitors of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), compositions thereof, and methods of using said compounds and compositions thereof. More specifically, the present disclosure relates to sulfoximine- based inhibitors of ENPP1 of Formula (I) and methods of their use for treating disease mediated by ENPP1.
