Synthesis and structure–activity relationships of imidazo[1,2-a]pyrimidin-5(1H)-ones as a novel series of beta isoform selective phosphatidylinositol 3-kinase inhibitors

Lin, Hong; Erhard, Karl F.; Hardwicke, Mary Ann; Luengo, Juan I.; Mack, James F.; McSurdy-Freed, Jeanelle; Plant, Ramona; Raha, Kaushik; Rominger, Cynthia M.; Sanchez, Robert M.; Schaber, Michael D.; Schulz, Mark J.; Spengler, Michael D.; Tedesco, Rosanna; Xie, Ren; Zhang, Jin; Rivero, Ralph A.

doi:10.1016/j.bmcl.2012.01.092

Cited by 39 publications

(36 citation statements)

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“…16,17 However, the compounds were not suitable for in vivo studies due to high clearance in rat and mouse. Both 1 and 2 contain an embedded benzylamine moiety, a potential site for metabolism, which might contribute to the high clearance.…”

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confidence: 99%

“…We were gratified to see that despite these potentially significant structural differences, both pyrazolopyrimidines retained the high PI3Kβ potency and excellent isoform selectivity observed with the other inhibitor series, as shown in Table 1. Because the SAR at this benzyl position had previously been well-established, 16 we were able to focus our further efforts mainly on the 2-methyl-3-trifluoromethyl benzyl analogues while we sought to better define the much less wellestablished hinge-binding and back-pocket SAR.…”

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confidence: 99%

“…A docking pose of 4a in a PI3Kβ homology model 16 is shown in Figure 2. The morpholine oxygen provides the key hydrogen-bonding interaction with the hinge residue Val 854 .…”

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confidence: 99%

“…The MDA-MB-468 cells are expected to be sensitive to PI3Kβ inhibition, while the HCC1954 cells should be much less sensitive and serve as a control cell line. Inhibition of proliferation was measured in an anchorage-independent (soft agar) growth assay, 16 and functional activity was determined by measuring inhibition of the PI3K-dependent phosphorylation of AKT at Ser 473 . 16,17 The cellular activity of selected compounds is shown in Table 5.…”

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confidence: 99%

“…Inhibition of proliferation was measured in an anchorage-independent (soft agar) growth assay, 16 and functional activity was determined by measuring inhibition of the PI3K-dependent phosphorylation of AKT at Ser 473 . 16,17 The cellular activity of selected compounds is shown in Table 5. Both the functional and the antiproliferative activities were unexpectedly poor for this entire class of compounds.…”

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[3a,4]-Dihydropyrazolo[1,5a]pyrimidines: Novel, Potent, and Selective Phosphatidylinositol-3-kinase β Inhibitors

Moore

Erhard

et al. 2013

ACS Med. Chem. Lett.

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A series of novel [3a,4]dihydropyrazolo[1,5a]-pyrimidines were identified, which were highly potent and selective inhibitors of PI3Kβ. The template afforded the opportunity to develop novel SAR for both the hinge-binding (R 3 ) and back-pocket (R 4 ) substitutents. While cellular potency was relatively modest due to high protein binding, the series displayed low clearance in rat, mouse, and monkey. KEYWORDS: PI3K-β inhibitor, PTEN-null, phosphatidylinositol-3-kinase, pyrazolopyrimidine, structure−activity relationship T he phosphatidylinositol 3-kinases (PI3Ks) are members of a larger family of lipid kinases that phosphorylate the inositol moiety of membrane-associated phosphatidyl inositols. 1 PI3Ks catalyze the conversion of phosphatidylinositol-4,5-diphosphate (PIP 2 ) to phosphatidylinositol-3,4,5-triphosphate (PIP 3 ), which allows recruitment of proteins containing the PIP 3 -binding pleckstrin homology (PH) domain to the plasma membrane. The PI3K class I family comprises four isoforms (α, β, δ, and γ), with the α and β isoforms most widely expressed. Each is a heterodimer consisting of an isoform-specific p110 catalytic subunit and a regulatory subunit.PI3Ks are an important mediator of receptor tyrosine kinase (RTK) and G-protein-coupled receptor (GPCR) signal transduction and are involved in the regulation of cellular metabolism, survival, and proliferation. 2 Aberrant activation of the PI3K pathway is strongly associated with malignant transformation, through either overexpression of PI3Kα, mutations that lead to constitutive activity of PI3Kα, or loss of function of the tumor suppressor PTEN (phosphatase and tensin homologue), which opposes PI3K function by converting PIP 3 to PIP 2 . 3−9 While the PI3K isoforms share the same substrate specificity, they have distinct biochemical roles and cellular functions. 10 In particular, there is considerable evidence that in PTEN-null tumors, malignant transformation is primarily driven by the PI3Kβ isoform. 11−15 The development of PI3Kβ-selective inhibitors is therefore an attractive target for the treatment of PTEN-null tumors.We have previously disclosed imidazopyrimidones (1) and triazolopyrimidones (2), as shown in Figure 1, which are potent and selective inhibitors of PI3Kβ. 16,17 However, the compounds were not suitable for in vivo studies due to high clearance in rat and mouse. Both 1 and 2 contain an embedded benzylamine moiety, a potential site for metabolism, which might contribute to the high clearance. We therefore designed a pyrazolo-pyrimidine scaffold, in which the benzyl group is attached to a carbon atom rather than a nitrogen, in an attempt to improve clearance.Pyrazolopyrimidines were generally prepared according to previously reported methods 18−20 as shown in Scheme 1. An α-cyanocarbonyl compound I is alkylated 21 with a benzyl bromide II and then condensed with hydrazine to afford the key aminopyrazole intermediate IV. The aminopyrazole is then condensed with a β-carbonyl-containing ester V to afford the 7-hydroxypyrazolopyrimi...

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confidence: 99%

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confidence: 99%

“…A docking pose of 4a in a PI3Kβ homology model 16 is shown in Figure 2. The morpholine oxygen provides the key hydrogen-bonding interaction with the hinge residue Val 854 .…”

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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[3a,4]-Dihydropyrazolo[1,5a]pyrimidines: Novel, Potent, and Selective Phosphatidylinositol-3-kinase β Inhibitors

Moore

Erhard

et al. 2013

ACS Med. Chem. Lett.

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Isoform Selective PI3K‐beta Inhibitors

Lin

2013

Chin. J. Chem.

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Although PI3K/AKT has undoubtedly been one of the most important pathways that impact tumorigenesis and proliferation, PI3K‐beta has not been considered as a stand‐alone target for potential cancer treatment until the recent discovery of the key role that PI3K‐beta plays in phosphatase and TENsin homolog (PTEN)‐deficient tumors. Medicinal chemistry efforts from the pharmaceutical industry and academia in the past few years have led to significant advancements in understanding beta isoform selectivity and in the development of a clinical drug candidate.

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New Imidazo[1,2‐c]pyrimidin‐5(6H)‐Ones Derived from Cytosine: Synthesis, Structure, and Cytotoxic Activity

Jansa

Lyčka

Padělková

et al. 2014

Journal of Heterocyclic Chem

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This work describes the synthesis of 8‐iodoimidazo[1,2‐c]pyrimidin‐5(6H)‐one 2 from 5‐iodocytosine 1. This compound was subjected to Suzuki cross‐coupling reaction with aryl and heteroarylboronic acids. After optimization, 10 products 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j were obtained in good yields 61‐90%. Cytotoxic activity of all new products was evaluated on seven tumor cell lines including resistant variants and on normal human fibroblasts. Two derivatives showed promising biological activity and good therapeutic index in the case of 3h.

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Synthesis and structure–activity relationships of imidazo[1,2-a]pyrimidin-5(1H)-ones as a novel series of beta isoform selective phosphatidylinositol 3-kinase inhibitors

Cited by 39 publications

References 20 publications

[3a,4]-Dihydropyrazolo[1,5a]pyrimidines: Novel, Potent, and Selective Phosphatidylinositol-3-kinase β Inhibitors

[3a,4]-Dihydropyrazolo[1,5a]pyrimidines: Novel, Potent, and Selective Phosphatidylinositol-3-kinase β Inhibitors

Isoform Selective PI3K‐beta Inhibitors

New Imidazo[1,2‐c]pyrimidin‐5(6H)‐Ones Derived from Cytosine: Synthesis, Structure, and Cytotoxic Activity

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