Dihydropyridine neuropeptide Y Y1 receptor antagonists 2. bioisosteric urea replacements.
Structure-activity studies around the urea linkage in BMS-193885 (4a) identified the cyanoguanidine moiety as an effective urea replacement in a series of dihydropyridine NPY Y(1) receptor antagonists. In comparison to urea 4a (K(i)=3.3 nM), cyanoguanidine 20 (BMS-205749) displayed similar binding potency at the Y(1) receptor (K(i)=5.1 nM) and full functional antagonism (K(b)=2.6 nM) in SK-N-MC cells. Cyanoguanidine 20 also demonstrated improved permeability properties in Caco-2 cells in comparison to urea 4a (43 vs 19 nm/s).
Poindexter
Graham S
GS
Pharmaceutical Research Institute, Bristol-Myers Squibb Co., 5 Research Parkway, Wallingford, CT 06492-7660, USA. graham.poindexter@bms.com
Bruce
Marc A
MA
Breitenbucher
J Guy
JG
Higgins
Mendi A
MA
Sit
S-Y
SY
Romine
Jeffrey L
JL
Martin
Scott W
SW
Ward
Sally A
SA
McGovern
Rachel T
RT
Clarke
Wendy
W
Russell
John
J
Antal-Zimanyi
Ildiko
I
D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006146:Guanidines / Q000737:chemistry; D006801:Humans; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry*
C456407:BMS 193885; D004095:Dihydropyridines; D006146:Guanidines; D010671:Phenylurea Compounds; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; C038806:1,4-dihydropyridine; D014508:Urea; C004711:dicyandiamido