Compounds > N-methyl-N-[2-[[[2-[(2-oxo-1-3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amino]methyl]phenyl]methanesulfonamide

N-methyl-N-[2-[[[2-[(2-oxo-1-3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amino]methyl]phenyl]methanesulfonamide and Osteoporosis

N-methyl-N-[2-[[[2-[(2-oxo-1-3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amino]methyl]phenyl]methanesulfonamide has been researched along with Osteoporosis* in 3 studies

Reviews

1 review(s) available for N-methyl-N-[2-[[[2-[(2-oxo-1-3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amino]methyl]phenyl]methanesulfonamide and Osteoporosis

Article	Year
Emerging targets in osteoporosis disease modification. Journal of medicinal chemistry, 2010, Jun-10, Volume: 53, Issue:11 Topics: Animals; Biomarkers; Bone Density; Bone Resorption; Humans; Osteoporosis	2010

Other Studies

2 other study(ies) available for N-methyl-N-[2-[[[2-[(2-oxo-1-3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amino]methyl]phenyl]methanesulfonamide and Osteoporosis

Article	Year
Sulfoximine-substituted trifluoromethylpyrimidine analogs as inhibitors of proline-rich tyrosine kinase 2 (PYK2) show reduced hERG activity. Bioorganic & medicinal chemistry letters, 2009, Jun-15, Volume: 19, Issue:12 The synthesis, in vitro properties, and in vivo pharmacokinetics for a series of sulfoximine-substituted trifluoromethylpyrimidines as inhibitors of proline-rich tyrosine kinase, a target for the possible treatment of osteoporosis, are described. These compounds were prepared as surrogates of the corresponding sulfone compound 1. Sulfone 1 was an attractive PYK2 lead compound; however, subsequent studies determined this compound possessed high dofetilide binding, which is an early indicator of cardiovascular safety. Surprisingly, the corresponding sulfoximine analogs displayed significantly lower dofetilide binding, which, for N-methylsulfoximine (S)-14a, translated to lower activity in a patch clamp hERG K(+) ion channel screen. In addition, compound (S)-14a shows good oral exposure in a rat pharmacokinetic model. Topics: Administration, Oral; Animals; Drug Evaluation, Preclinical; Enzyme Inhibitors; Ether-A-Go-Go Potassium Channels; Focal Adhesion Kinase 2; Humans; Imines; Osteoporosis; Patch-Clamp Techniques; Phenethylamines; Pyrimidines; Rats; Structure-Activity Relationship; Sulfonamides; Sulfones	2009
Trifluoromethylpyrimidine-based inhibitors of proline-rich tyrosine kinase 2 (PYK2): structure-activity relationships and strategies for the elimination of reactive metabolite formation. Bioorganic & medicinal chemistry letters, 2008, Dec-01, Volume: 18, Issue:23 The synthesis and SAR for a series of diaminopyrimidines as PYK2 inhibitors are described. Using a combination of library and traditional medicinal chemistry techniques, a FAK-selective chemical series was transformed into compounds possessing good PYK2 potency and 10- to 20-fold selectivity against FAK. Subsequent studies found that the majority of the compounds were positive in a reactive metabolite assay, an indicator for potential toxicological liabilities. Based on the proposed mechanism for bioactivation, as well as a combination of structure-based drug design and traditional medicinal chemistry techniques, a follow-up series of PYK2 inhibitors was identified that maintained PYK2 potency, FAK selectivity and HLM stability, yet were negative in the RM assay. Topics: Animals; Combinatorial Chemistry Techniques; Crystallography, X-Ray; Disease Models, Animal; Drug Design; Focal Adhesion Kinase 2; Focal Adhesion Protein-Tyrosine Kinases; Humans; Molecular Conformation; Molecular Structure; Osteoporosis; Pyrimidines; Rats; Structure-Activity Relationship	2008

Article

Year

Sulfoximine-substituted trifluoromethylpyrimidine analogs as inhibitors of proline-rich tyrosine kinase 2 (PYK2) show reduced hERG activity.

Bioorganic & medicinal chemistry letters, 2009, Jun-15, Volume: 19, Issue:12

The synthesis, in vitro properties, and in vivo pharmacokinetics for a series of sulfoximine-substituted trifluoromethylpyrimidines as inhibitors of proline-rich tyrosine kinase, a target for the possible treatment of osteoporosis, are described. These compounds were prepared as surrogates of the corresponding sulfone compound 1. Sulfone 1 was an attractive PYK2 lead compound; however, subsequent studies determined this compound possessed high dofetilide binding, which is an early indicator of cardiovascular safety. Surprisingly, the corresponding sulfoximine analogs displayed significantly lower dofetilide binding, which, for N-methylsulfoximine (S)-14a, translated to lower activity in a patch clamp hERG K(+) ion channel screen. In addition, compound (S)-14a shows good oral exposure in a rat pharmacokinetic model.

Topics: Administration, Oral; Animals; Drug Evaluation, Preclinical; Enzyme Inhibitors; Ether-A-Go-Go Potassium Channels; Focal Adhesion Kinase 2; Humans; Imines; Osteoporosis; Patch-Clamp Techniques; Phenethylamines; Pyrimidines; Rats; Structure-Activity Relationship; Sulfonamides; Sulfones

2009

Trifluoromethylpyrimidine-based inhibitors of proline-rich tyrosine kinase 2 (PYK2): structure-activity relationships and strategies for the elimination of reactive metabolite formation.

Bioorganic & medicinal chemistry letters, 2008, Dec-01, Volume: 18, Issue:23

The synthesis and SAR for a series of diaminopyrimidines as PYK2 inhibitors are described. Using a combination of library and traditional medicinal chemistry techniques, a FAK-selective chemical series was transformed into compounds possessing good PYK2 potency and 10- to 20-fold selectivity against FAK. Subsequent studies found that the majority of the compounds were positive in a reactive metabolite assay, an indicator for potential toxicological liabilities. Based on the proposed mechanism for bioactivation, as well as a combination of structure-based drug design and traditional medicinal chemistry techniques, a follow-up series of PYK2 inhibitors was identified that maintained PYK2 potency, FAK selectivity and HLM stability, yet were negative in the RM assay.

Topics: Animals; Combinatorial Chemistry Techniques; Crystallography, X-Ray; Disease Models, Animal; Drug Design; Focal Adhesion Kinase 2; Focal Adhesion Protein-Tyrosine Kinases; Humans; Molecular Conformation; Molecular Structure; Osteoporosis; Pyrimidines; Rats; Structure-Activity Relationship

2008