Novel dihydropyrazine analogues as NPY antagonists.
The dihydropyridine is currently one of the lead compounds in the neuropeptide-Y(1) (NPY-Y(1)) receptor antagonist program. Compound is a selective, high affinity ligand at the NPY-Y(1) receptors (IC(50)=4.2 nM) in SK-N-MC cells. To further expand the SAR study surrounding this dihydropyridine core structure we succeeded in synthesizing an analogous series of dihydropyrazine derivatives. This structural modification yielded compounds substantially different from the parent molecules in terms of molecular polarization and electron distribution while the overall molecular structure was generally preserved. This altered property should therefore provide us with additional SAR information on the optimal binding requirement with NPY receptors.
Sit
Sing-Yuen
SY
Department of Neuroscience/Genitourinary Drug Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492-7660, USA. sits@bms.com
Huang
Yazhong
Y
Antal-Zimanyi
Ildiko
I
Ward
Sally
S
Poindexter
Graham S
GS
D018360:Crystallography, X-Ray; D003500:Cyclization; D006801:Humans; D013058:Mass Spectrometry; D009478:Neuropeptide Y / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D009478:Neuropeptide Y; D011719:Pyrazines; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor