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Your search keyword '"Gunawardane RN"' showing total 3 results
Start Over Author "Gunawardane RN" Topic protein kinase inhibitors
3 results on '"Gunawardane RN"'

1. 4-Quinazolinyloxy-diaryl ureas as novel BRAFV600E inhibitors.

Author

Holladay MW, Campbell BT, Rowbottom MW, Chao Q, Sprankle KG, Lai AG, Abraham S, Setti E, Faraoni R, Tran L, Armstrong RC, Gunawardane RN, Gardner MF, Cramer MD, Gitnick D, Ator MA, Dorsey BD, Ruggeri BR, Williams M, Bhagwat SS, and James J

Subjects
Animals, Dose-Response Relationship, Drug, Mice, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Quinazolines chemical synthesis, Quinazolines chemistry, Rats, Stereoisomerism, Structure-Activity Relationship, Tissue Distribution, Urea analogs & derivatives, Urea chemistry, Xenograft Model Antitumor Assays, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Proto-Oncogene Proteins B-raf metabolism, Quinazolines pharmacology, Urea pharmacology
Abstract

Aryl phenyl ureas with a 4-quinazolinoxy substituent at the meta-position of the phenyl ring are potent inhibitors of mutant and wild type BRAF kinase. Compound 7 (1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea hydrochloride) exhibits good pharmacokinetic properties in rat and mouse and is efficacious in a mouse tumor xenograft model following oral dosing., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2011
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2. Identification of N-(5-tert-butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS-like tyrosine kinase-3 (FLT3) inhibitor.

Author

Chao Q, Sprankle KG, Grotzfeld RM, Lai AG, Carter TA, Velasco AM, Gunawardane RN, Cramer MD, Gardner MF, James J, Zarrinkar PP, Patel HK, and Bhagwat SS

Subjects
Animals, Benzothiazoles chemical synthesis, Benzothiazoles chemistry, Benzothiazoles pharmacokinetics, Cell Line, Tumor, Drug Evaluation, Preclinical, Female, Humans, Male, Mice, Phenylurea Compounds chemical synthesis, Phenylurea Compounds chemistry, Phenylurea Compounds pharmacokinetics, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacokinetics, Rats, Solubility, Substrate Specificity, Xenograft Model Antitumor Assays, Benzothiazoles pharmacology, Phenylurea Compounds pharmacology, Protein Kinase Inhibitors pharmacology, fms-Like Tyrosine Kinase 3 antagonists & inhibitors
Abstract

Treatment of AML patients with small molecule inhibitors of FLT3 kinase has been explored as a viable therapy. However, these agents are found to be less than optimal for the treatment of AML because of lack of sufficient potency or suboptimal oral pharmacokinetics (PK) or lack of adequate tolerability at efficacious doses. We have developed a series of extremely potent and highly selective FLT3 inhibitors with good oral PK properties. The first series of compounds represented by 1 (AB530) was found to be a potent and selective FLT3 kinase inhibitor with good PK properties. The aqueous solubility and oral PK properties at higher doses in rodents were found to be less than optimal for clinical development. A novel series of compounds were designed lacking the carboxamide group of 1 with an added water solubilizing group. Compound 7 (AC220) was identified from this series to be the most potent and selective FLT3 inhibitor with good pharmaceutical properties, excellent PK profile, and superior efficacy and tolerability in tumor xenograft models. Compound 7 has demonstrated a desirable safety and PK profile in humans and is currently in phase II clinical trials.

Published
2009
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3. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML).

Author

Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B, Karaman MW, Pratz KW, Pallares G, Chao Q, Sprankle KG, Patel HK, Levis M, Armstrong RC, James J, and Bhagwat SS

Subjects
Animals, Benzenesulfonates pharmacology, Benzothiazoles pharmacokinetics, Bone Marrow drug effects, Bone Marrow pathology, Carbazoles pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, Female, Furans, Humans, Mice, Mice, Nude, Mice, SCID, Niacinamide analogs & derivatives, Phenylurea Compounds pharmacokinetics, Phosphorylation drug effects, Piperazines pharmacology, Prognosis, Protein Interaction Mapping, Protein Kinase C antagonists & inhibitors, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacokinetics, Pyridines pharmacology, Quinazolines pharmacology, Sorafenib, Staurosporine analogs & derivatives, Staurosporine pharmacology, Xenograft Model Antitumor Assays, Benzothiazoles pharmacology, Leukemia, Myeloid, Acute drug therapy, Phenylurea Compounds pharmacology, Protein Kinase Inhibitors pharmacology, fms-Like Tyrosine Kinase 3 antagonists & inhibitors
Abstract

Activating mutations in the receptor tyrosine kinase FLT3 are present in up to approximately 30% of acute myeloid leukemia (AML) patients, implicating FLT3 as a driver of the disease and therefore as a target for therapy. We report the characterization of AC220, a second-generation FLT3 inhibitor, and a comparison of AC220 with the first-generation FLT3 inhibitors CEP-701, MLN-518, PKC-412, sorafenib, and sunitinib. AC220 exhibits low nanomolar potency in biochemical and cellular assays and exceptional kinase selectivity, and in animal models is efficacious at doses as low as 1 mg/kg given orally once daily. The data reveal that the combination of excellent potency, selectivity, and pharmacokinetic properties is unique to AC220, which therefore is the first drug candidate with a profile that matches the characteristics desirable for a clinical FLT3 inhibitor.

Published
2009
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