title: Dihydropyridine neuropeptide Y Y1 receptor antagonists 2. bioisosteric urea replacements.
abstract: 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).
authors.affiliation: Pharmaceutical Research Institute, Bristol-Myers Squibb Co., 5 Research Parkway, Wallingford, CT 06492-7660, USA. graham.poindexter@bms.com
authors.forename: Graham S
authors.initials: GS
authors.lastname: Poindexter
authors.forename: Marc A
authors.initials: MA
authors.lastname: Bruce
authors.forename: J Guy
authors.initials: JG
authors.lastname: Breitenbucher
authors.forename: Mendi A
authors.initials: MA
authors.lastname: Higgins
authors.forename: S-Y
authors.initials: SY
authors.lastname: Sit
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Romine
authors.forename: Scott W
authors.initials: SW
authors.lastname: Martin
authors.forename: Sally A
authors.initials: SA
authors.lastname: Ward
authors.forename: Rachel T
authors.initials: RT
authors.lastname: McGovern
authors.forename: Wendy
authors.initials: W
authors.lastname: Clarke
authors.forename: John
authors.initials: J
authors.lastname: Russell
authors.forename: Ildiko
authors.initials: I
authors.lastname: Antal-Zimanyi
mesh_terms: 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*
chemical_list: 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