Purpose: Osimertinib is a potent and selective EGFR tyrosine kinase inhibitor (EGFR-TKI) of both sensitizing and T790M resistance mutations. To treat metastatic brain disease, blood–brain barrier (BBB) permeability is considered desirable for increasing clinical efficacy. Experimental Design: We examined the level of brain penetration for 16 irreversible and reversible EGFR-TKIs using multiple in vitro and in vivo BBB preclinical models. Results: In vitro osimertinib was the weakest substrate for human BBB efflux transporters (efflux ratio 3.2). In vivo rat free brain to free plasma ratios (Kpuu) show osimertinib has the most BBB penetrance (0.21), compared with the other TKIs (Kpuu ≤ 0.12). PET imaging in Cynomolgus macaques demonstrated osimertinib was the only TKI among those tested to achieve significant brain penetrance (Cmax %ID 1.5, brain/blood Kp 2.6). Desorption electrospray ionization mass spectroscopy images of brains from mouse PC9 macrometastases models showed osimertinib readily distributes across both healthy brain and tumor tissue. Comparison of osimertinib with the poorly BBB penetrant afatinib in a mouse PC9 model of subclinical brain metastases showed only osimertinib has a significant effect on rate of brain tumor growth. Conclusions: These preclinical studies indicate that osimertinib can achieve significant exposure in the brain compared with the other EGFR-TKIs tested and supports the ongoing clinical evaluation of osimertinib for the treatment of EGFR-mutant brain metastasis. This work also demonstrates the link between low in vitro transporter efflux ratios and increased brain penetrance in vivo supporting the use of in vitro transporter assays as an early screen in drug discovery.
The reaction of the σ-bonded (PCP)Pd-Me complex (PCP = 2,6-bis [(di-tert-butylphosphino)methyl]phenyl) with CO 2 is first-order in palladium and first-order in CO 2 with a rate constant k s = 8.9 ( 0.8 M -1 s -1 at 353 K. Activation parameters are ΔH q = 73 ( 7 kJ/mol and ΔS q = -118 ( 19 J/K mol. Based on this and theoretical calculations we propose an S E 2 mechanism where the coordinated methyl group attacks a completely noncoordinated carbon dioxide molecule in a bimolecular reaction. The PCPPd-crotyl complex was synthesized in an 65:35 E:Z mixture, and it was shown to react with CO 2 to give the complex PCPPd-O(CO)CH(CH 3 )CHCH 2 as a single isomer, where the former γ-carbon has been carboxylated. Theoretical calculations again suggest an S E 2 mechanism with a noncoordinated carbon dioxide reacting with the terminal carbon on the allyl group, forming an η 2 -bonded olefin complex as an intermediate. The rearrangement of this intermediate to the O-bonded product is concluded to be rate determining. The crystal structure of PCPPd-O(CO)C(CH 3 ) 2 CHCH 2 is reported and as well as the solubility of carbon dioxide in benzene-d 6 at different pressures and temperatures.
Arynes derived from any position of the ubiquitous indole nucleus are unknown. We have now provided the first evidence for the formation and trapping of the 4,5-, 5,6-, and 6,7-indolynes. A series of o-dihalo indoles (Cl, Br, F) were synthesized and reacted under metal-halogen exchange conditions to give Diels-Alder cycloadducts in high yield with furan. The use of an excess of tert-butyllithium resulted in the rearrangement of the initially formed cycloadduct; however, employing only a slight excess of n-butyllithium cleanly gave cycloadducts with furan.
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