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Kinase_Lecture_MedChem2

Salts spacer allows morpholine to protrude out of the

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Unformatted text preview: 5nib (Iressa) Kinase inhibitors based on ATP Gefi5nib (Iressa): isostere of adenosine halogena5on prevents metabolism by CYP morpholine helps to solubilize the compound Gefi4nib (Iressa) Lead compound Secondary amine HN 4 N CH3 6 Small lipophilic group OMe Electron-donating substituents N 7 OMe I; IC50 5 nM Notes • The secondary amine, electron- dona4ng subs4tuents and small lipophilic group are all important for ac4vity • Useful in vitro ac4vity • Lower in vivo ac4vity due to rapid metabolism • Metabolised by cytochrome P450 enzymes Gefi4nib (Iressa) Metabolism of the lead compound OH HN 4 N N CH3 6 OMe 7 OMe I; IC50 5 nM Cytochrome P450 enzymes Oxida4on HN OH OMe N HN + OMe N N II OMe CH3 N OMe III Notes • Methyl group and para- posi4on of aroma4c ring are suscep4ble posi4ons • Blocking metabolism should improve the half life of the drug Gefi4nib (Iressa) Drug design F HN 4 N CH3 6 HN OMe OMe N N 7 I; IC50 5 nM OMe Cl N OMe IV: IC50 9 nM Notes • Fluoro- subs4tuent blocks para- hydroxyla4on of the aroma4c ring • Fluorine is similar in size to hydrogen and ha...
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