Novel pyrazolo[1,5-a]pyrimidines as c-Src kinase inhibitors that reduce IKr channel blockade. 2008

Harunobu Mukaiyama, and Toshihiro Nishimura, and Satoko Kobayashi, and Yoshimitsu Komatsu, and Shinji Kikuchi, and Tomonaga Ozawa, and Noboru Kamada, and Hideki Ohnota
Central Research Laboratory, Kissei Pharmaceutical Company Ltd, 4365-1, Azumino-city, Nagano 399-8304, Japan. harunobu_mukaiyama@pharm.kissei.co.jp

To improve the in vitro potency of the c-Src inhibitor 1a and to address its hERG liability, a structure-activity study was carried out, focusing on two regions of the lead compound. The blockade of the delayed cardiac current rectifier K(+) (I(Kr)) channel was overcome by replacing the ethylenediamino group with an amino alcohol group at the 7-position. In addition, modifying the substituents at the 5-position and the side chain groups on the amino alcohols at the 7-position enhanced the intracellular c-Src inhibitory activity and increased central nervous system (CNS) penetration. In the present study, 6l exhibited significant in vivo efficacy in a middle cerebral artery (MCA) occlusion model in rats.

UI MeSH Term Description Entries
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D008968 Molecular Conformation The characteristic three-dimensional shape of a molecule. Molecular Configuration,3D Molecular Structure,Configuration, Molecular,Molecular Structure, Three Dimensional,Three Dimensional Molecular Structure,3D Molecular Structures,Configurations, Molecular,Conformation, Molecular,Conformations, Molecular,Molecular Configurations,Molecular Conformations,Molecular Structure, 3D,Molecular Structures, 3D,Structure, 3D Molecular,Structures, 3D Molecular
D011720 Pyrazoles Azoles of two nitrogens at the 1,2 positions, next to each other, in contrast with IMIDAZOLES in which they are at the 1,3 positions.
D011743 Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular
D051381 Rats The common name for the genus Rattus. Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus
D019061 src-Family Kinases A PROTEIN-TYROSINE KINASE family that was originally identified by homology to the Rous sarcoma virus ONCOGENE PROTEIN PP60(V-SRC). They interact with a variety of cell-surface receptors and participate in intracellular signal transduction pathways. Oncogenic forms of src-family kinases can occur through altered regulation or expression of the endogenous protein and by virally encoded src (v-src) genes. Protein-Tyrosine Kinases, src,Src Family Tyrosine Kinase,src Kinase,src Kinases,src Tyrosine Kinase,src-Family Kinase,src-Family Tyrosine Kinase,src Tyrosine Kinases,src-Family Tyrosine Kinases,Kinase, src,Kinase, src Tyrosine,Kinase, src-Family,Kinase, src-Family Tyrosine,Kinases, src,Kinases, src Protein-Tyrosine,Kinases, src Tyrosine,Tyrosine Kinase, src,Tyrosine Kinase, src-Family,Tyrosine Kinases, src,Tyrosine Kinases, src-Family,src Family Kinase,src Family Kinases,src Family Tyrosine Kinases,src Protein-Tyrosine Kinases
D020650 Combinatorial Chemistry Techniques A technology, in which sets of reactions for solution or solid-phase synthesis, is used to create molecular libraries for analysis of compounds on a large scale. Chemistry Techniques, Combinatorial,Techniques, Combinatorial Chemistry,Chemistry Technic, Combinatorial,Chemistry Technics, Combinatorial,Chemistry Technique, Combinatorial,Combinatorial Chemistry Technic,Combinatorial Chemistry Technics,Combinatorial Chemistry Technique,Technic, Combinatorial Chemistry,Technics, Combinatorial Chemistry,Technique, Combinatorial Chemistry
D020768 Middle Cerebral Artery The largest of the cerebral arteries. It trifurcates into temporal, frontal, and parietal branches supplying blood to most of the parenchyma of these lobes in the CEREBRAL CORTEX. These are the areas involved in motor, sensory, and speech activities. Cerebral Artery, Middle,Arteries, Middle Cerebral,Artery, Middle Cerebral,Cerebral Arteries, Middle,Middle Cerebral Arteries

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