title: Non-peptide alpha(v)beta(3) antagonists: identification of potent, chain-shortened RGD mimetics that incorporate a central pyrrolidinone constraint.
abstract: Antagonists of the integrin receptor alpha(v)beta(3) are expected to have utility in the treatment of osteoporosis through inhibition of bone resorption. A series of potent, chain-shortened, pyrrolidinone-containing alpha(v)beta(3) receptor antagonists is described. Two sets of diasteromeric pairs of high-affinity antagonists demonstrated marked differences in log P values, which translated into differing dog pharmacokinetic properties. One member of this set was demonstrated to be effective in reducing bone resorption in rats.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Perkins
authors.forename: L T
authors.initials: LT
authors.lastname: Duong
authors.forename: Carmen
authors.initials: C
authors.lastname: Fernandez-Metzler
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Donald B
authors.initials: DB
authors.lastname: Kimmel
authors.forename: Chih Tai
authors.initials: CT
authors.lastname: Leu
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: Gideon A
authors.initials: GA
authors.lastname: Rodan
authors.forename: Sevgi B
authors.initials: SB
authors.lastname: Rodan
authors.forename: Mark E
authors.initials: ME
authors.lastname: Duggan
authors.forename: Robert S
authors.initials: RS
authors.lastname: Meissner
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D011760:Pyrrolidinones / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D011760:Pyrrolidinones