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Your search keyword '"Zalameda L"' showing total 3 results
Start Over Author "Zalameda L" Topic class i phosphatidylinositol 3-kinases
3 results on '"Zalameda L"'

1. Synthesis and SAR study of potent and selective PI3Kδ inhibitors.

Author

Bui M, Hao X, Shin Y, Cardozo M, He X, Henne K, Suchomel J, McCarter J, McGee LR, San Miguel T, Medina JC, Mohn D, Tran T, Wannberg S, Wong J, Wong S, Zalameda L, Metz D, and Cushing TD

Subjects
Animals, Class I Phosphatidylinositol 3-Kinases metabolism, Humans, Male, Protein Isoforms antagonists & inhibitors, Protein Isoforms metabolism, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacokinetics, Quinolines chemical synthesis, Quinolines pharmacokinetics, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Class I Phosphatidylinositol 3-Kinases antagonists & inhibitors, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Quinolines chemistry, Quinolines pharmacology
Abstract

2,3,4-Substituted quinolines such as (10a) were found to be potent inhibitors of PI3Kδ in both biochemical and cellular assays with good selectivity over three other class I PI3K isoforms. Some of those analogs showed favorable pharmacokinetic properties., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Published
2015
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2. Discovery and in vivo evaluation of (S)-N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and related PI3Kδ inhibitors for inflammation and autoimmune disease.

Author

Cushing TD, Hao X, Shin Y, Andrews K, Brown M, Cardozo M, Chen Y, Duquette J, Fisher B, Gonzalez-Lopez de Turiso F, He X, Henne KR, Hu YL, Hungate R, Johnson MG, Kelly RC, Lucas B, McCarter JD, McGee LR, Medina JC, San Miguel T, Mohn D, Pattaropong V, Pettus LH, Reichelt A, Rzasa RM, Seganish J, Tasker AS, Wahl RC, Wannberg S, Whittington DA, Whoriskey J, Yu G, Zalameda L, Zhang D, and Metz DP

Subjects
Adenosine chemistry, Adenosine metabolism, Animals, Cells, Cultured, Class I Phosphatidylinositol 3-Kinases chemistry, Class I Phosphatidylinositol 3-Kinases metabolism, Crystallography, X-Ray, Disease Models, Animal, Drug Discovery, Female, Humans, Mice, Inbred BALB C, Mice, Transgenic, Models, Chemical, Models, Molecular, Molecular Structure, Protein Binding, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors metabolism, Protein Structure, Tertiary, Quinolines chemistry, Quinolines metabolism, Rats, Inbred Lew, Sf9 Cells, Structure-Activity Relationship, Adenosine pharmacology, Autoimmune Diseases prevention & control, Class I Phosphatidylinositol 3-Kinases antagonists & inhibitors, Inflammation prevention & control, Protein Kinase Inhibitors pharmacology, Quinolines pharmacology
Abstract

The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.

Published
2015
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3. Structure-based design of a novel series of potent, selective inhibitors of the class I phosphatidylinositol 3-kinases.

Author

Smith AL, D'Angelo ND, Bo YY, Booker SK, Cee VJ, Herberich B, Hong FT, Jackson CL, Lanman BA, Liu L, Nishimura N, Pettus LH, Reed AB, Tadesse S, Tamayo NA, Wurz RP, Yang K, Andrews KL, Whittington DA, McCarter JD, Miguel TS, Zalameda L, Jiang J, Subramanian R, Mullady EL, Caenepeel S, Freeman DJ, Wang L, Zhang N, Wu T, Hughes PE, and Norman MH

Subjects
Animals, Biological Availability, Class I Phosphatidylinositol 3-Kinases physiology, Crystallography, X-Ray, Drug Design, Female, Humans, Indazoles chemical synthesis, Indazoles pharmacokinetics, Indazoles pharmacology, Mice, Mice, Nude, Microsomes, Liver metabolism, Models, Molecular, Piperazines pharmacokinetics, Piperazines pharmacology, Proto-Oncogene Proteins c-akt physiology, Purines chemical synthesis, Purines pharmacokinetics, Purines pharmacology, Pyrazoles chemical synthesis, Pyrazoles pharmacokinetics, Pyrazoles pharmacology, Pyridines pharmacokinetics, Pyridines pharmacology, Pyrimidines chemical synthesis, Pyrimidines pharmacokinetics, Pyrimidines pharmacology, Rats, Signal Transduction, Structure-Activity Relationship, Sulfonamides pharmacokinetics, Sulfonamides pharmacology, Sulfones chemical synthesis, Sulfones pharmacokinetics, Sulfones pharmacology, TOR Serine-Threonine Kinases antagonists & inhibitors, Triazines pharmacokinetics, Triazines pharmacology, Xenograft Model Antitumor Assays, Class I Phosphatidylinositol 3-Kinases antagonists & inhibitors, Piperazines chemical synthesis, Pyridines chemical synthesis, Sulfonamides chemical synthesis, Triazines chemical synthesis
Abstract

A highly selective series of inhibitors of the class I phosphatidylinositol 3-kinases (PI3Ks) has been designed and synthesized. Starting from the dual PI3K/mTOR inhibitor 5, a structure-based approach was used to improve potency and selectivity, resulting in the identification of 54 as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases. Compound 54 demonstrated a robust PD-PK relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and it potently inhibited tumor growth in a U-87 MG xenograft model with an activated PI3K/Akt pathway.

Published
2012
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