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Your search keyword '"Sarah E. Lively"' showing total 5 results
Start Over Author "Sarah E. Lively" Topic molecular medicine
5 results on '"Sarah E. Lively"'

1. Metabolism-guided discovery of a potent and orally bioavailable urea-based calcimimetic for the treatment of secondary hyperparathyroidism

Author

Pierre Deprez, Paul M. Wehn, Jeff D. Reagan, Minghan Wang, Paul E. Harrington, Mark P. Grillo, Kanaka Pattabiraman, James Davis, Charles Henley, Sean Morony, Taoues Temal, Christopher H. Fotsch, Steve F. Poon, Timothy J. Carlson, David J. St. Jean, Sarah E. Lively, Yuhua Yang, and Jenny Ying-Lin Lu

Subjects
Male, Calcimimetic, Metabolite, Clinical Biochemistry, Administration, Oral, Biological Availability, Pharmaceutical Science, Pharmacology, Biochemistry, Rats, Sprague-Dawley, chemistry.chemical_compound, Pharmacokinetics, In vivo, Drug Discovery, medicine, Animals, Urea, Potency, Molecular Biology, CYP3A4, Organic Chemistry, medicine.disease, Rats, Bioavailability, Thiazoles, chemistry, Parathyroid Hormone, Molecular Medicine, Hyperparathyroidism, Secondary, Secondary hyperparathyroidism, Receptors, Calcium-Sensing, Half-Life, Protein Binding
Abstract

A series of urea based calcimimetics was optimized for potency and oral bioavailability. Crucial to this process was overcoming the poor pharmacokinetic properties of lead thiazole 1. Metabolism-guided modifications, characterized by the use of metabolite identification (ID) and measurement of time dependent inhibition (TDI) of CYP3A4, were essential to finding a compound suitable for oral dosing. Calcimimetic 18 exhibited excellent in vivo potency in a 5/6 nephrectomized rat model and cross-species pharmacokinetics.

Published
2013

2. New potent calcimimetics: II. Discovery of benzothiazole trisubstituted ureas

Author

Helene Jary, Pierre Deprez, Denis Guédin, Taoues Temal, Marielle Auberval, Sarah E. Lively, and Jean-Paul Vevert

Subjects
Stereochemistry, Calcimimetic, Organic Chemistry, Clinical Biochemistry, Allosteric regulation, Pharmaceutical Science, Pharmacology, Biochemistry, chemistry.chemical_compound, chemistry, Benzothiazole, Oral administration, In vivo, Drug Discovery, Urea, Molecular Medicine, Calcium, Luciferase, Benzothiazoles, Calcium-sensing receptor, Receptors, Calcium-Sensing, Molecular Biology
Abstract

Following the identification of trisubstituted ureas as a promising new chemical series of allosteric modulators of the calcium sensing receptor (CaSR), we further explored the SAR around the urea substitution, leading to the discovery of benzothiazole urea compound 13. This compound is a potent calcimimetic with an EC50 = 20 nM (luciferase assay). Evaluated in an in vivo model of chronic renal failure (short term and long term in 5/6 nephrectomized rats), benzothiazole urea 13 significantly decreased PTH levels after oral administration while keeping calcemia within the normal range.

Published
2013

3. Discovery of potent, selective, and orally bioavailable inhibitors of interleukin-1 receptor-associate kinase-4

Author

Zhaodan Cao, Zhulun Wang, Xiong Gao, Shichang Miao, Nigel Walker, Daqing Sun, Jingqian Liu, Xuelei Yan, Juan C. Jaen, Jay P. Powers, Sheree Johnstone, Matt Wright, Sarah E. Lively, Craig Tomooka, Athena Sudom, and Qiuping Ye

Subjects
Benzimidazole, Clinical Biochemistry, Pharmaceutical Science, Administration, Oral, Plasma protein binding, Interleukin-1 receptor, Biochemistry, Enzyme activator, chemistry.chemical_compound, Structure-Activity Relationship, Interleukin-1 Receptor-Associated Kinases, Drug Discovery, Structure–activity relationship, Animals, Molecular Biology, Protein Kinase Inhibitors, Molecular Structure, Kinase, Drug discovery, Organic Chemistry, Rats, Enzyme Activation, chemistry, Molecular Medicine, Benzimidazoles, Protein Binding
Abstract

In this Letter, we report the continued optimization of the N-acyl-2-aminobenzimidazole series, focusing in particular on the N-alkyl substituent and 5-position of the benzimidazole based on the binding mode and the early SAR. These efforts led to the discovery of 16, a highly potent, selective, and orally bioavailable inhibitor of IRAK-4.

Published
2015

4. Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3

Author

Mei-Chu Lo, Ji Ma, Julio C. Medina, Dineli Wickramasinghe, Mark L. Ragains, Derek E. Piper, Merrill Ayres, Zhihong Li, Alex J. Zhang, Xiaoqi Chen, Jeffrey Deignan, Zhulun Wang, Kanaka Pattabiraman, Kathleen S. Keegan, Xiaoning Zhao, Rachel Ngo, Nigel Walker, Lingming Liang, Margaret F. Weidner, Paul M. Wehn, Christophe Queva, Jason Duquette, Alexander Kamb, Ada Chen, Malgorzata Wanska, Jeffrey T. Mihalic, Kriti Modi, Pingchen Fan, Grace Q. Alba, Yunxiao Li, Michael W. Gribble, John Eksterowicz, Jacob Kaizerman, Dustin McMinn, Xianghong Wang, Michael DeGraffenreid, Steve Thibault, Xiaodong Wang, Kexue Li, Benjamin Fisher, Richard V. Connors, Wen Liu, Sarah E. Lively, Cong Li, Kang Dai, Jiasheng Fu, Justin N. Huard, Robert Cho, Lawrence R. McGee, Timothy J. Carlson, and Julia Suchomel

Subjects
Programmed cell death, Pyrimidine, Cell, chemistry.chemical_compound, Structure-Activity Relationship, Dogs, Drug Discovery, medicine, Animals, Cytochrome P-450 CYP3A, Humans, Naphthyridines, Protein Kinase Inhibitors, STAT5, biology, Chemistry, Kinase, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, U937 Cells, Rats, Macaca fascicularis, medicine.anatomical_structure, Biochemistry, fms-Like Tyrosine Kinase 3, Cell culture, biology.protein, Molecular Medicine, Cytochrome P-450 CYP3A Inhibitors, Growth inhibition, Lead compound, Heterocyclic Compounds, 3-Ring
Abstract

We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.

Published
2014

5. New potent calcimimetics: I. Discovery of a series of novel trisubstituted ureas

Author

Sarah E. Lively, Jean-Paul Vevert, Helene Jary, Denis Guédin, Pierre Deprez, Marielle Auberval, and Taoues Temal

Subjects
Fendiline, Stereochemistry, Organic Chemistry, Clinical Biochemistry, Allosteric regulation, Substituent, Pharmaceutical Science, medicine.disease, Biochemistry, In vitro, chemistry.chemical_compound, Structure-Activity Relationship, chemistry, In vivo, Biomimetic Materials, Drug Discovery, Urea, medicine, Molecular Medicine, Secondary hyperparathyroidism, Calcium, Calcium-sensing receptor, Molecular Biology, Receptors, Calcium-Sensing
Abstract

Starting from Fendiline and R-568, we identified a novel series of urea compounds as positive allosteric modulators of the calcium sensing receptor (CaSR), as part of a program to identify novel therapeutics for secondary hyperparathyroidism. Initially identified disubstituted ureas were converted to trisubstituted urea lead 20e, which was further modified to increase in vivo potency. Replacing a carbomethoxy substituent by various bioisosteres led to compound 46 which exhibited potent in vitro and in vivo activity after oral administration.

Published
2012

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