Discovery of Novel and Orally Bioavailable Inhibitors of PI3 Kinase Based on Indazole Substituted Morpholino-Triazines

Abstract

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.

Recent Advances in the Development of Indazole‐based Anticancer Agents

“…Starting from hit 44 (IC 50 value of 900 n m against PI3Kα), Dugar et al. characterized dozens of indazole‐substituted morpholino‐triazine derivatives as PI3K inhibitors through multistep optimization (Figure ) . Considering that the morpholine is a critical moiety for interacting with the hinge region Val 882 residue of the PI3K protein, their attentions were primarily shifted to the phenolic group and glycine moiety.…”

“…Startingf rom hit 44 (IC 50 value of 900 nm against PI3Ka), Dugar et al characterized dozens of indazole-substituted morpholino-triazine derivatives as PI3K inhibitors through multistep optimization ( Figure 17). [78] Considering that the morpholine is ac riticalm oiety for interacting with the hinge region Val882 residue of the PI3K protein, their attentions were primarily shiftedt ot he phenolic group and glycine moiety.A fter af irst round of optimization, compound 45 was selected for furtheri mprovementb ased on its potency against PI3Ka (IC 50 value of 540 nm). Drivenb yagenerally accepted observation that ap henol moiety would impart poor pharmacokinetic properties to ac ompound,a uthors drew their attention to modifying the phenol moiety.C oincidentally,c ompound 46, bearinga ni ndazole ring, was found to be the most suitable alternatet op henol with am inimall oss of potency (IC 50 value of 1100 nm).…”

The Drug Discovery and Development Industry in India—Two Decades of Proprietary Small‐Molecule R&D

“…The company filed a first patent in 2011 on PI3K/mTOR inhibitors,334 of which one, SPR965, has reached the preclinical evaluation stage 335, 336. The compound is likely to be structurally related, if not identical to a compound recently described in a publication 337. In 2015, Sphaera announced a collaboration with the International Centre for Genetic Engineering and Biotechnology (ICGEB), funded by the Wellcome Trust for the development of inhibitors of niacin receptor 1 (NIACR1), also known as GPR109A, to treat multidrug‐resistant infections, that led to SPR113 which entered preclinical development (Supporting Information Table 6a, entries 205–206) 338, 339, 340…”

“…[335,336] The compound is likely to be structurally related, if not identicalt oac ompound recently described in ap ublication. [337] In 2015, Sphaera announced ac ollaboration with the International Centre for Genetic Engineering and Biotechnology (ICGEB), funded by the WellcomeT rust for the development of inhibitors of niacin receptor1 (NIACR1), also knowna sG PR109A, to treat multidrug-resistanti nfections, that led to SPR113 which enteredpreclinical development (Supporting Information Table 6a, entries [205][206]. [338][339][340] Curadev was founded 2010 in Noida, and currently employs around5 0p eople.…”

Direct Catalytic Functionalization of Indazole Derivatives

“…[8] In particular, Indazoles acted as selective estrogen receptor degraders, [9][10] farnesold-X receptor agonist, [11] selective 5-HT2 receptor, [12] liver X receptor agonist, [13] selective CRAF inhibitors, [14] viral polymerase inhibitor, [15] anticancer agents [16] mostly as multi kinase inhibitor, [17] FGFR inhibitors, [18] Aurora A kinase [19] and some other type of kinase inhibitors. [20][21][22][23] Indazoles have strong affinity for 5-HT 1A receptor β and I 2 receptor. Some of the indazole derivatives are used as important drugs such as ABT-102 (A) [24] is used for chronic pain, granisetron (B) [25][26] is used as antiemetic in cancer chemotherapy, bendazac (C) [27] is used as anticataract agent, benzydamine (D) [28] is used as anti-inflammatory agent, niraparib (E) [29] is widely used as an anticancer drug for the treatment of recurrent epithelial ovarian, fallopian tube or primary peritoneal, breast and prostate cancer.…”