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Start Over Author "Durley RC" Journal bioorganic medicinal chemistry letters
4 results on '"Durley RC"'

1. Design, synthesis and activity of a potent, selective series of N-aryl pyridinone inhibitors of p38 kinase.

Author

Selness SR, Boehm TL, Walker JK, Devadas B, Durley RC, Kurumbail R, Shieh H, Xing L, Hepperle M, Rucker PV, Jerome KD, Benson AG, Marrufo LD, Madsen HM, Hitchcock J, Owen TJ, Christie L, Promo MA, Hickory BS, Alvira E, Naing W, Blevis-Bal R, Devraj RV, Messing D, Schindler JF, Hirsch J, Saabye M, Bonar S, Webb E, Anderson G, and Monahan JB

Subjects
Animals, Disease Models, Animal, Enzyme Activation drug effects, Enzyme Inhibitors chemistry, Humans, Inhibitory Concentration 50, Male, Microsomes, Liver enzymology, Molecular Structure, Pyridazines chemistry, Pyridazines pharmacology, Pyridones chemistry, Pyrimidines chemistry, Pyrimidines pharmacology, Rats, Rats, Sprague-Dawley, Drug Design, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Pyridones chemical synthesis, Pyridones pharmacology, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
Abstract

A series of N-aryl pyridinone inhibitors of p38 mitogen activated protein (MAP) kinase were designed and prepared based on the screening hit SC-25028 (1) and structural comparisons to VX-745 (5). The focus of the investigation targeted the dependence of potency and metabolic stability on the benzyloxy connectivity, the role of the C-6 position and the substitution pattern on the N-phenyl ring. Further optimization produced the highly selective and potent pyridinones 2 and 3. These inhibitors exhibited activity in both acute and chronic models of inflammation., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2011
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2. Discovery of PH-797804, a highly selective and potent inhibitor of p38 MAP kinase.

Author

Selness SR, Devraj RV, Devadas B, Walker JK, Boehm TL, Durley RC, Shieh H, Xing L, Rucker PV, Jerome KD, Benson AG, Marrufo LD, Madsen HM, Hitchcock J, Owen TJ, Christie L, Promo MA, Hickory BS, Alvira E, Naing W, Blevis-Bal R, Messing D, Yang J, Mao MK, Yalamanchili G, Vonder Embse R, Hirsch J, Saabye M, Bonar S, Webb E, Anderson G, and Monahan JB

Subjects
Animals, Benzamides chemistry, Disease Models, Animal, Dogs, Enzyme Activation drug effects, Enzyme Inhibitors chemistry, Humans, Inhibitory Concentration 50, Macaca fascicularis, Male, Molecular Structure, Pyridones, Pyrones chemistry, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, p38 Mitogen-Activated Protein Kinases chemistry, p38 Mitogen-Activated Protein Kinases pharmacology, Benzamides chemical synthesis, Benzamides pharmacology, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Pyrones chemical synthesis, Pyrones pharmacology, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
Abstract

The synthesis and SAR studies of a novel N-aryl pyridinone class of p38 kinase inhibitors are described. Systematic structural modifications to the HTS lead, 5, led to the identification of (-)-4a as a clinical candidate for the treatment of inflammatory diseases. Additionally, the chiral synthesis and properties of (-)-4a are described., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2011
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3. Discovery of N-substituted pyridinones as potent and selective inhibitors of p38 kinase.

Author

Selness SR, Devraj RV, Monahan JB, Boehm TL, Walker JK, Devadas B, Durley RC, Kurumbail R, Shieh H, Xing L, Hepperle M, Rucker PV, Jerome KD, Benson AG, Marrufo LD, Madsen HM, Hitchcock J, Owen TJ, Christie L, Promo MA, Hickory BS, Alvira E, Naing W, and Blevis-Bal R

Subjects
Administration, Oral, Animals, Anti-Inflammatory Agents chemical synthesis, Anti-Inflammatory Agents pharmacokinetics, Binding Sites, Catalytic Domain, Crystallography, X-Ray, Drug Discovery, Humans, JNK Mitogen-Activated Protein Kinases antagonists & inhibitors, JNK Mitogen-Activated Protein Kinases metabolism, Male, Microsomes, Liver metabolism, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacokinetics, Pyridones chemical synthesis, Pyridones pharmacokinetics, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, p38 Mitogen-Activated Protein Kinases metabolism, Anti-Inflammatory Agents chemistry, Protein Kinase Inhibitors chemistry, Pyridones chemistry, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
Abstract

The identification and evolution of a series of potent and selective p38 inhibitors is described. p38 inhibitors based on a N-benzyl pyridinone high-throughput screening hit were prepared and their SAR explored. Their design was guided by ligand bound co-crystals of p38alpha. These efforts resulted in the identification of 12r and 19 as orally active inhibitors of p38 with significant efficacy in both acute and chronic models of inflammation.

Published
2009
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4. Novel heteroaryl replacements of aromatic 3-tetrafluoroethoxy substituents in trifluoro-3-(tertiaryamino)-2-propanols as potent inhibitors of cholesteryl ester transfer protein.

Author

Massa MA, Spangler DP, Durley RC, Hickory BS, Connolly DT, Witherbee BJ, Smith ME, and Sikorski JA

Subjects
Cholesterol Ester Transfer Proteins, Carrier Proteins antagonists & inhibitors, Glycoproteins, Propanols chemistry, Propanols pharmacology
Abstract

A series of novel N,N-disubstituted trifluoro-3-amino-2-propanols has been prepared as potent inhibitors of cholesteryl ester transfer protein (CETP). Modifying the aromatic 3-tetrafluoroethoxy group in the lead molecule 1a with various heteroaryl moieties produced new 2-furyl analogues 2a,b with submicromolar potency in vitro.

Published
2001
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