Preparation
Stumpf et al. at Genentech Inc. (Roche group) developed an efficient multikilogram process to synthesize the brain penetrant PI3K inhibitor, GDC?\0084, a potential drug candidate for the treatment of several brain cancers. An efficient Suzuki coupling reaction between a chloropyrimidine and an arylboronic ester using a palladium catalyst at low loading was reported. The optimized conditions were demonstrated on 6.75 kg of a chloropyrimidine intermediate, providing 7.49 kg of crude GDC?\0084 (94% yield, 99.4% HPLC purity). Using the commercially available XPhos Pd G2 catalyst, instead of the usual PdCl2(dppf)·CH2Cl2 catalyst, it was possible to reduce the catalyst loading from 2 to 0.5 mol%. A final scavenging/recrystallization combination from Si?\Thiol (a solid?\supported resin) and acetic acid/water provided the crude GDC?\0084 with the required purity and polymorphic form (off?\white solid, 6.41 kg, 83% yield, 99.7% HPLC purity).
Genentech’s route to GDC?\0084 employing a pivotal Suzuki reaction.
Biological Activity
gdc-0084 is a potent and brain penetrant inhibitor of pi3k and mtor with ki values of 2 nm and 70 nm for pi3kα and mtor, respectively [1].glioblastoma (gbm) is the most common primary brain tumor in adults and aberrant pi3k signaling is associated with more than 80% of cases. the pi3k pathway represents a potential target for the treatment of this disease and the inhibitors would need to freely cross the blood-brain barrier (bbb) [1][2].gdc-0084 is a potent and brain penetrant inhibitor of pi3k and mtor. in vitro kinase assay, gdc-0084 exhibited ki values of 2 nm, 46 nm, 3 nm, 10 nm and 70 nm for pi3kα, pi3kβ, pi3kδ, pi3kγ and mtor, respectively. in five different gbm cell lines, gdc-0084 had antiproliferative activities with ec50 values ranging from 0.3 to 1.1 μm. gdc-0084 has excellent human metabolic stability in microsomal and hepatocyte incubations [1]. in transfected cell lines over-expressing human or mouse p-gp or bcrp, gdc-0084 was a poor substrate of these efflux transporters. in mice brain, gdc-0084 significantly lowered pakt and ps6 levels [2].in rats after a 15 mg/kg dose of gdc-0084, the total brain-to-plasma ratio was 1.9-3.3. in subcutaneous u87 glioblastoma tumor xenograft mice model, gdc-0084 significantly inhibited tumor growth in a dose-dependent way. gdc-0084 also concentration-dependently inhibited pakt [1].[1]. heffron tp1, ndubaku co1, salphati l1, et al. discovery of clinical development candidate gdc-0084, a brain penetrant inhibitor of pi3k and mtor. acs med chem lett. 2016 feb 16;7(4):351-6.[2]. salphati l, alicke b, heffron tp, et al. brain distribution and efficacy of the brain penetrant pi3k inhibitor gdc-0084 in orthotopic mouse models of human glioblastoma. drug metab dispos. 2016 dec;44(12):1881-1889. epub 2016 sep 16.
