title: Understanding DP receptor antagonism using a CoMSIA approach.
abstract: A Comparative Molecular Similarity Indices Analysis (CoMSIA) was performed for 2,6-substituted-4-monosubstituted aminopyrimidine antagonists of prostaglandin D(2) receptor (DP). Both two-component (Q(2) = 0.63, R(2) = 0.82, SEE = 0.47 pIC(50)) and three-component (Q(2) = 0.70, R(2) = 0.91, SEE = 0.36 pIC(50)) CoMSIA models were established. Two hydrogen-bond acceptors with spatial separation of about 8Å are shown as optimal for binding. A large hydrophobic center that separates the two acceptors confers to the potency of the 2,6-substituted-4-monosubstituted aminopyrimidine. The models were used to predict IC(50) values for compounds which had functional groups different from those in the training set.
authors.affiliation: Sanofi Aventis US, 1041 Route 202-206 N, Bridgewater, NJ 08807-0800, United States.
authors.forename: Lan
authors.initials: L
authors.lastname: Mu
authors.forename: Joacy
authors.initials: J
authors.lastname: Aguiar
authors.forename: Ali
authors.initials: A
authors.lastname: Ardati
authors.forename: Bin
authors.initials: B
authors.lastname: Cao
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Gardner
authors.forename: Tim
authors.initials: T
authors.lastname: Gillespy
authors.forename: Keith
authors.initials: K
authors.lastname: Harris
authors.forename: Sungtaek
authors.initials: S
authors.lastname: Lim
authors.forename: Robert
authors.initials: R
authors.lastname: Marcus
authors.forename: Isabelle
authors.initials: I
authors.lastname: Morize
authors.forename: Ashfaq
authors.initials: A
authors.lastname: Parkar
authors.forename: David
authors.initials: D
authors.lastname: Stefany
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Roy J
authors.initials: RJ
authors.lastname: Vaz
authors.forename: Dragan A
authors.initials: DA
authors.lastname: Cirovic
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C036293:prostaglandin D2 receptor