Synthetic studies on novel Syk inhibitors. Part 1: Synthesis and structure-activity relationships of pyrimidine-5-carboxamide derivatives.
Spleen tyrosine kinase (Syk) is a non-receptor-type tyrosine kinase which mediates diverse responses in haematopoietic cells. Therefore, Syk is an attractive therapeutic target, and in a study of Syk inhibitors as potentially new therapeutic agents, we discovered the 4-anilinopyrimidine-5-carboxamides. Enzyme screening indicated that an aminoethylamino moiety at the 2-position of the pyrimidine ring was important for Syk inhibitory activity, and an investigation of the substituents at the 4-position revealed that an anilino moiety substituted at the meta position was preferred. These compounds showed high selectivity for Syk, compared to other kinases, such as ZAP-70, c-Src, and PKC, and exhibited good inhibitory activities against 5-HT release from RBL-cells. Among them, compound 9a inhibited the passive cutaneous anaphylaxis reaction in mice, with an ID50 of 13 mg/kg following subcutaneous administration. These results suggest that our compounds are worthy of further evaluation as new anti-allergic agents.
Institute for Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. hiroyuki.hisamichi@jp.astellas.com
Hiroyuki
H
Hisamichi
Ryo
R
Naito
Akira
A
Toyoshima
Noriyuki
N
Kawano
Atsushi
A
Ichikawa
Akiko
A
Orita
Masaya
M
Orita
Noritaka
N
Hamada
Makoto
M
Takeuchi
Mitsuaki
M
Ohta
Shin-ichi
S
Tsukamoto
D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D000072377:Syk Kinase
D000577:Amides; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse