Inhibitors of epidermal growth factor receptor tyrosine kinase: Optimisation of potency and in vivo pharmacokinetics

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 18, 2006, Pages 4908-4912

  Ballard, Peter ^a   Bradbury, Robert H ^a   Harris, Craig S ^a   Hennequin, Laurent F A ^a   Hickinson, Mark ^a   Kettle, Jason G ^a   Kendrew, Jane ^a   Klinowska, Teresa ^a   Ogilvie, Donald J ^a   Pearson, Stuart E ^a   Williams, Emma J ^a   Wilson, Ingrid ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

DMPK; EGF; Inhibitor; Kinase

Indexed keywords

EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; GEFITINIB; N (4 BROMO 2 FLUOROPHENYL) 6 METHOXY 7 [2 (1H 1,2,3 TRIAZOL 1 YL)ETHOXY] 4 QUINAZOLINAMINE; QUINAZOLINE DERIVATIVE; VANDETANIB;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CANCER INHIBITION; CLINICAL TRIAL; COLON CANCER; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG HALF LIFE; DRUG POTENCY; FEMALE; HUMAN; IN VIVO STUDY; LUNG NON SMALL CELL CANCER; MODULATION; NONHUMAN; PKA; RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL LINE, TUMOR; CHEMISTRY, PHYSICAL; FLUORINE; HUMANS; INHIBITORY CONCENTRATION 50; MICE; MOLECULAR STRUCTURE; NEOPLASMS; PROTEIN KINASE INHIBITORS; QUINAZOLINES; RATS; RECEPTOR, EPIDERMAL GROWTH FACTOR; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLES; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 33747035894     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.06.054     Document Type: Article

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16. The rat pharmacokinetic data reported in this paper are from a protocol designed to allow high throughput profiling of compounds and as such are non-optimised. Literature data for 1 (see Ref. 8) show some variance with the data in Table 2 due to the more detailed nature, and differing protocols used in these studies. {A figure is presented}
17. While the clearance figure of 129 ml/min/kg is seemingly at odds with the reported bioavailability of 74%, it should be noted that this is for clearance of drug from plasma. This basic compound partitions extensively into blood, such that the blood clearance is a more realistic 65 ml/min/kg. Nevertheless, the good bioavailability observed may reflect saturation of first-pass clearance, or other non-hepatic routes of elimination.