443882-99-3Relevant articles and documents
Discovery of novel and potent safinamide-based derivatives as highly selective hMAO-B inhibitors for treatment of Parkinson's disease (PD): Design, synthesis, in vitro, in vivo and in silico biological studies
Elkamhawy, Ahmed,Hassan, Ahmed H. E.,Kim, Hyeon Jeong,Lee, Kyeong,Paik, Sora,Park, Jong-Hyun,Park, Ki Duk,Roh, Eun Joo
, (2021/08/16)
Up to date, the current clinical practice employs only symptomatic treatments for management of Parkinson's disease (PD) but unable to stop disease progression. The discovery of new chemical entities endowed with potent and selective human monoamine oxidase B (hMAO-B) inhibitory activity is a clinically relevant subject. Herein, a structural optimization strategy for safinamide (a well-known second generation hMAO-B inhibitor) afforded a series of thirty-six safinamide-derived new analogs (4aa–bj). Most compounds showed promising inhibitory activities against hMAO-B (>70% inhibition at a single dose concentration of 10 μM), with no apparent effect on hMAO-A at 100 μM. Moreover, while six compounds (4ak, 4as, 4az, 4be, 4bg, and 4bi) exhibited potent double-digit nanomolar activities over hMAO-B with IC50 values of 29.5, 42.2, 22.3, 18.8, 42.2, and 33.9 nM, respectively, three derivatives (4aq, 4at, and 4bf), possessing the same carboxamide moiety (2-pyrazinyl), showed the most potent single-digit nanomolar activities (IC50 = 9.7, 5.1, and 3.9 nM, respectively). Compound 4bf revealed an excellent selectivity index (SI > 25641) with a 29-fold increase compared to safinamide (SI > 892). A structure activity relationship along with molecular docking simulations provided insights into enzyme ? inhibitor interactions and a rational for the observed activity. In an in vivo MPTP-induced mouse model of PD, oral administration of compound 4bf significantly protected nigrostriatal dopaminergic neurons as revealed by tyrosine hydroxylase staining and prevented MPTP-induced Parkinsonism as revealed by motor behavioral assays. Accordingly, we present compound 4bf as a novel, highly potent, and selective hMAO-B inhibitor with an effective therapeutic profile for relieving PD.
HER2 Kinase-Targeted Breast Cancer Therapy: Design, Synthesis, and in Vitro and in Vivo Evaluation of Novel Lapatinib Congeners as Selective and Potent HER2 Inhibitors with Favorable Metabolic Stability
Elwaie, Tamer A.,Abbas, Safinaz E.,Aly, Enayat I.,George, Riham F.,Ali, Hamdy,Kraiouchkine, Nikolai,Abdelwahed, Khaldoun S.,Fandy, Tamer E.,El Sayed, Khalid A.,Abd Elmageed, Zakaria Y.,Ali, Hamed I.
, p. 15906 - 15945 (2021/01/09)
HER2 kinase as a well-established target for breast cancer (BC) therapy is associated with aggressive clinical outcomes; thus, herein we present structural optimization for HER2-selective targeting. HER2 profiling of the developed derivatives demonstrated
Surmounting the resistance against EGFR inhibitors through the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors
Milik, Sandra N.,Abdel-Aziz, Amal Kamal,Lasheen, Deena S.,Serya, Rabah A.T.,Minucci, Saverio,Abouzid, Khaled A.M.
supporting information, p. 316 - 336 (2018/06/14)
In light of the emergence of resistance against the currently available EGFR inhibitors, our study focuses on tackling this problem through the development of dual EGFR/HER2 inhibitors with improved enzymatic affinities. Guided by the binding mode of the
