Dugar Sundeep, Hollinger Frank P, Mahajan Dinesh, Sen Somdutta, Kuila Bilash, Arora Reena, Pawar Yogesh, Shinde Vaibhav, Rahinj Mahesh, Kapoor Kamal K, Bhumkar Rahul, Rai Santosh, Kulkarni Rakesh
Sphaera Pharma Pte. Ltd. , 038988, Singapore.
Sphaera Pharma Pvt. Ltd. , Plot 32, Sec 5, IMT Manesar, Harayana 122051, India.
ACS Med Chem Lett. 2015 Nov 2;6(12):1190-4. doi: 10.1021/acsmedchemlett.5b00322. eCollection 2015 Dec 10.
A new class of potent PI3Kα inhibitors is identified based on aryl substituted morpholino-triazine scaffold. The identified compounds showed not only a high level of enzymatic and cellular potency in nanomolar range but also high oral bioavailability. The three lead molecules (based on their in vitro potency) when evaluated further for in vitro metabolic stability as well as pharmacokinetic profile led to the identification of 26, as a candidate for further development. The IC50 and EC50 value of 26 is 60 and 500 nM, respectively, for PI3Kα enzyme inhibitory activity and ovarian cancer (A2780) cell line. The identified lead also showed a high level of microsomal stability and minimal inhibition activity for CYP3A4, CYP2C19, and CYP2D6 at 10 μM concentrations. The lead compound 26, demonstrated excellent oral bioavailability with an AUC of 5.2 μM at a dose of 3 mpk in mice and found to be well tolerated in mice when dosed at 30 mpk BID for 5 days.
基于芳基取代的吗啉代三嗪支架，鉴定出了一类新型的强效PI3Kα抑制剂。所鉴定的化合物不仅在纳摩尔范围内表现出高水平的酶活性和细胞活性，而且具有高口服生物利用度。对三个先导分子（基于其体外活性）进一步评估其体外代谢稳定性以及药代动力学特征后，确定26作为进一步开发的候选物。对于PI3Kα酶抑制活性和卵巢癌（A2780）细胞系，26的IC50和EC50值分别为60和500 nM。所鉴定的先导物在10 μM浓度下还表现出高水平的微粒体稳定性以及对CYP3A4、CYP2C19和CYP2D6的最小抑制活性。先导化合物26在小鼠中以3 mpk的剂量给药时，AUC为5.2 μM，显示出优异的口服生物利用度，并且在以30 mpk BID的剂量给药5天时，在小鼠中耐受性良好。
