Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors

Peterson, Emily A.; Boezio, Alessandro A.; Andrews, Paul S.; Boezio, Christiane; Bush, Tammy L.; Cheng, Alan C.; Choquette, Deborah M.; Coats, James; Colletti, Adria; Copeland, Katrina W.; DuPont, Michelle M.; Graceffa, Russell F.; Grubinska, Barbara; Kim, Joseph L.; Lewis, Richard T.; Liu, Jingzhou; Mullady, Erin L.; Potashman, Michele; Romero, Karina; Shaffer, Paul; Stanton, Mary K.; Stellwagen, John; Teffera, Yohannes; Yi, Shuyan; Cai, Ti; La, Daniel S.

doi:10.1016/j.bmcl.2012.06.033

Cited by 36 publications

(26 citation statements)

References 16 publications

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“…Compound 1 (.98% purity) was synthesized by the Medicinal Chemistry Department at Amgen, Inc. (Cambridge, MA) (Peterson et al, 2012). [ 14 C]-compound 1 (57.5 mci/mmol) was obtained from Moravek Biochemicals, Inc. (Brea, CA).…”

Section: Methodsmentioning

confidence: 99%

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Species Difference in Glucuronidation Formation Kinetics with a Selective mTOR Inhibitor

et al. 2014

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The mammalian target of rapamycin (mTOR) is a protein kinase that shows key involvement in age-related disease and promises to be a target for treatment of cancer. In the present study, the elimination of potent ATP-competitive mTOR inhibitor 3-(6-amino-2-methylpyrimidin-4-yl)-N-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-amine (compound 1) is studied in bile duct-cannulated rats, and the metabolism of compound 1 in liver microsomes is compared across species. Compound 1 was shown to undergo extensive N-glucuronidation in bile duct-catheterized rats. N-glucuronides were detected on positions N1 (M2) and N2 (M1) of the pyrazole moiety as well as on the primary amine (M3). All three N-glucuronide metabolites were detected in liver microsomes of the rat, dog, and human, while primary amine glucuronidation was not detected in cynomolgus monkey. In addition, N1-and N2-glucuronidation showed strong species selectivity in vitro, with rat, dog, and human favoring N2-glucuronidation and monkey favoring N1-glucuronide formation. Formation of M1 in monkey liver microsomes also followed sigmoidal kinetics, singling out monkey as unique among the species with regard to compound 1 N-glucuronidation. In this respect, monkeys might not always be the best animal model for N-glucuronidation of uridine diphosphate glucuronosyltransferase (UGT) 1A9 or UGT1A1 substrates in humans. The impact of N-glucuronidation of compound 1 could be more pronounced in higher species such as monkey and human, leading to high clearance in these species. While compound 1 shows promise as a candidate for investigating the impact of pan-mTOR inhibition in vivo, opportunities may exist through medicinal chemistry efforts to reduce metabolic liability with the goal of improving systemic exposure.

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Section: Methodsmentioning

confidence: 99%

“…Previously, Peterson et al (2012) described the discovery of a series of selective imidazopyridazine mTOR inhibitors. In particular, compound 1 (Fig.…”

Section: Introductionmentioning

confidence: 99%

Species Difference in Glucuronidation Formation Kinetics with a Selective mTOR Inhibitor

et al. 2014

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“…mTOR is validated as an anticancer therapy target in clinical study [46][47][48][49]. The mTOR pathway regulates growth factor signaling, recognizes cellular nutrients and energy availably, and eventually mediates cell functions depending on two distinct multi-protein complexes, mTOR complex 1(mTORC1) and mTOR complex 2 (mTORC2) [50]. mTORC1 phosphorylates the substrates 4EBP1 and S6K in cell translation and growth, whereas mTORC2 phosphorylates S473 to activate AKT signaling.…”

Section: 3 5-triazine Derivatives Targeting Mtormentioning

confidence: 99%

“…mTORC1 phosphorylates the substrates 4EBP1 and S6K in cell translation and growth, whereas mTORC2 phosphorylates S473 to activate AKT signaling. Both of them are in charge of PI3K/AKT pathway wherein signaling ingredients usually mutate in cancer cells [50]. The most appealing treatment with cancer is targeting mTOR kinase in the past few years [51].…”

Section: 3 5-triazine Derivatives Targeting Mtormentioning

confidence: 99%

“…The IC 50 against PI3K-γ was 1256 nM (2730-fold selective). Besides, 12 was supposed to inhibit a panel of 21 kinases without IC 50 's below 50 μM (>100,000-fold selectivity). The low clearance (0.0083 mL/min/million cells) and high half-life (>60 min) of compound 12 verified the significant stability in human hepatocytes as well as human microsome.…”

Section: 3 5-triazine Derivatives Targeting Mtormentioning

confidence: 99%

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A Systematic Review on Antitumor Agents with 1, 3, 5-triazines

Liu¹

2015

Med chem

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Synthesis and Evaluation of Imidazo[1,2‐a]pyridine Analogues of the ZSTK474 Class of Phosphatidylinositol 3‐Kinase Inhibitors

Gamage

Spicer

Tsang

et al. 2019

Chemistry An Asian Journal

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Using a scaffold‐hopping approach, imidazo[1,2‐a]pyridine analogues of the ZSTK474 (benzimidazole) class of phosphatidylinositol 3‐kinase (PI3K) inhibitors have been synthesized for biological evaluation. Compounds were prepared using a heteroaryl Heck reaction procedure, involving the palladium‐catalysed coupling of 2‐(difluoromethyl)imidazo[1,2‐a]pyridines with chloro, iodo or trifluoromethanesulfonyloxy (trifloxy) substituted 1,3,5‐triazines or pyrimidines, with the iodo intermediates being preferred in terms of higher yields and milder reaction conditions. The new compounds maintain the PI3K isoform selectivity of their benzimidazole analogues, but in general show less potency.

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Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors

Cited by 36 publications

References 16 publications

Species Difference in Glucuronidation Formation Kinetics with a Selective mTOR Inhibitor

Species Difference in Glucuronidation Formation Kinetics with a Selective mTOR Inhibitor

A Systematic Review on Antitumor Agents with 1, 3, 5-triazines

Synthesis and Evaluation of Imidazo[1,2‐a]pyridine Analogues of the ZSTK474 Class of Phosphatidylinositol 3‐Kinase Inhibitors

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