Synthesis and evaluation of pyridazinylpiperazines as vanilloid receptor 1 antagonists.
A structurally biased chemical library of pyridazinylpiperazine analogs was prepared in an effort to improve the pharmaceutical and pharmacological profile of the lead compound N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide (BCTC). The library was evaluated for VR1 antagonist activity in capsaicin-induced (CAP) and pH5.5-induced (pH) FLIPR assays in a human VR1-expressing HEK293 cell line. The most potent VR1 antagonists were found to have IC(50) values in the range of 9-200nM with improved pharmaceutical and pharmacological profiles versus the lead BCTC. These compounds represent possible second-generation BCTC analogs.
Tafesse
Laykea
L
Discovery Research, Purdue Pharma L.P., 6 Cedar, Brook Drive, Cranbury, NJ 08512, USA. laykea.tafesse@pharma.com
Sun
Qun
Q
Schmid
Lori
L
Valenzano
Kenneth J
KJ
Rotshteyn
Yakov
Y
Su
Xin
X
Kyle
Donald J
DJ
D000818:Animals; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D006801:Humans; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011955:Receptors, Drug / Q000037:antagonists & inhibitors*; D050916:TRPV Cation Channels; D013997:Time Factors
C475772:N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide; D010879:Piperazines; D011719:Pyrazines; D011724:Pyridazines; D011725:Pyridines; D011955:Receptors, Drug; D050916:TRPV Cation Channels; C494484:TRPV1 receptor