Optimization of a series of multi-isoform PI3 kinase inhibitors

Perry, Benjamin; Beevers, Rebekah E.; Bennett, Gavin; Buckley, George M.; Crabbe, Thomas; Gowers, Lewis; James, L A; Jenkins, Kerry; Lock, Chris M.; Sabin, Verity; Wright, S. Kirk

doi:10.1016/j.bmcl.2008.08.042

Cited by 9 publications

(6 citation statements)

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“…To increase selectivity and aqueous solubility, the next generation of inhibitors led to compounds 5 and 6. 53 These compounds showed improved pharmacokinetic properties and efficacy in oral dosing upon testing against an inflammation model to measure acute T-cell activation (5, ED 50 = 5 mg/kg).…”

Section: Benzoxazine Derivativesmentioning

confidence: 99%

Inhibitors of phosphoinositide-3-kinase: a structure-based approach to understanding potency and selectivity

2009

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Section: Benzoxazine Derivativesmentioning

confidence: 99%

Inhibitors of phosphoinositide-3-kinase: a structure-based approach to understanding potency and selectivity

2009

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“…UCB Celltech Co. reported a series of 5,5-dimethyl-2-morpholin-4-yl-5,6-dihydro-1,3-benzothiazol-7(4 H )-ones ( 93 – 96 , Figure ) as specific inhibitors of PI3K isoforms p110γ and -δ. − Surprisingly, modification of the initial pharmacophore ( 93 ) was performed on the morpholine ring, which is not usually tolerated. Substitution on the central dihydrobenzothiazole core was not beneficial in term of potency except for the replacement of the carbonyl group at position 6 with a lactam ( 95 , 96 ) to improve physicochemical properties.…”

Section: Pi3k Inhibitorsmentioning

confidence: 99%

“…Compound 96 is the result of further optimization focused on cellular activity, selectivity, and solubility, having IC 50 values of 4 and 20 nM for p110γ and -δ, respectively. Both of these compounds ( 95 , 96 ) possess favorable pharmacokinetic profiles for oral administration, and they are promising agents for chronic inflammatory disease therapy …”

Section: Pi3k Inhibitorsmentioning

confidence: 99%

“…Both of these compounds (95,96) possess pharmacokinetic profiles for oral administration, and they are promising agents for chronic inflammatory disease therapy. 219 The tetrasubstituted thiophene 97, Pfizer Co., is the result of a structure-based drug design and optimization approach. 220 This derivative showed enhanced and specific p110α inhibition (p110α and mTOR IC 50 values of 0.35 nM and 2.5 μM, respectively) and improved pharmacokinetic properties for oral administration.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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Phosphatidylinositol 3-Kinase (PI3K) and Phosphatidylinositol 3-Kinase-Related Kinase (PIKK) Inhibitors: Importance of the Morpholine Ring

et al. 2014

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Phosphatidylinositol 3-kinases (PI3Ks) and phosphatidylinositol 3-kinase-related protein kinases (PIKKs) are two related families of kinases that play key roles in regulation of cell proliferation, metabolism, migration, survival, and responses to diverse stresses including DNA damage. To design novel efficient strategies for treatment of cancer and other diseases, these kinases have been extensively studied. Despite their different nature, these two kinase families have related origin and share very similar kinase domains. Therefore, chemical inhibitors of these kinases usually carry analogous structural motifs. The most common feature of these inhibitors is a critical hydrogen bond to morpholine oxygen, initially present in the early nonspecific PI3K and PIKK inhibitor 3 (LY294002), which served as a valuable chemical tool for development of many additional PI3K and PIKK inhibitors. While several PI3K pathway inhibitors have recently shown promising clinical responses, inhibitors of the DNA damage-related PIKKs remain thus far largely in preclinical development.

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“…Inhibitor 99 has an ED 50 of 5 mg/kg in a rat in vivo model of CD3 induced IL-2 release. 173 Wilex has partnered with UCB to develop WX-037 (structure not disclosed), a dual PI3Kδ/α inhibitor for solid tumors. Millennium has disclosed thiazole 100 and thiophene 101 for targeting inflammation.…”

Section: ■ Pi3kδ Selective Inhibitorsmentioning

confidence: 99%