title: 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.
authors.affiliation: Sphaera Pharma Pte. Ltd. , 038988, Singapore.
authors.forename: Sundeep
authors.initials: S
authors.lastname: Dugar
authors.affiliation: Sphaera Pharma Pte. Ltd. , 038988, Singapore.
authors.forename: Frank P
authors.initials: FP
authors.lastname: Hollinger
authors.affiliation: Sphaera Pharma Pvt. Ltd. , Plot 32, Sec 5, IMT Manesar, Harayana 122051, India.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Mahajan
authors.affiliation: Sphaera Pharma Pvt. Ltd. , Plot 32, Sec 5, IMT Manesar, Harayana 122051, India.
authors.forename: Somdutta
authors.initials: S
authors.lastname: Sen
authors.affiliation: Sphaera Pharma Pvt. Ltd. , Plot 32, Sec 5, IMT Manesar, Harayana 122051, India.
authors.forename: Bilash
authors.initials: B
authors.lastname: Kuila
authors.affiliation: Sphaera Pharma Pvt. Ltd. , Plot 32, Sec 5, IMT Manesar, Harayana 122051, India.
authors.forename: Reena
authors.initials: R
authors.lastname: Arora
authors.affiliation: Sphaera Pharma Pvt. Ltd. , Plot 32, Sec 5, IMT Manesar, Harayana 122051, India.
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Pawar
authors.affiliation: Sphaera Pharma Pvt. Ltd. , Plot 32, Sec 5, IMT Manesar, Harayana 122051, India.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Shinde
authors.affiliation: Sphaera Pharma Pvt. Ltd. , Plot 32, Sec 5, IMT Manesar, Harayana 122051, India.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Rahinj
authors.affiliation: Sphaera Pharma Pvt. Ltd. , Plot 32, Sec 5, IMT Manesar, Harayana 122051, India.
authors.forename: Kamal K
authors.initials: KK
authors.lastname: Kapoor
authors.affiliation: Sphaera Pharma Pvt. Ltd. , Plot 32, Sec 5, IMT Manesar, Harayana 122051, India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Bhumkar
authors.affiliation: Sphaera Pharma Pvt. Ltd. , Plot 32, Sec 5, IMT Manesar, Harayana 122051, India.
authors.forename: Santosh
authors.initials: S
authors.lastname: Rai
authors.affiliation: Sphaera Pharma Pvt. Ltd. , Plot 32, Sec 5, IMT Manesar, Harayana 122051, India.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kulkarni
keywords: Cancer; PI3K inhibitors; indazole; morpholinotriazine