Non-peptide alpha(v)beta(3) antagonists: identification of potent, chain-shortened RGD mimetics that incorporate a central pyrrolidinone constraint.
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.
Perkins
James J
JJ
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
Duong
L T
LT
Fernandez-Metzler
Carmen
C
Hartman
George D
GD
Kimmel
Donald B
DB
Leu
Chih Tai
CT
Lynch
Joseph J
JJ
Prueksaritanont
Thomayant
T
Rodan
Gideon A
GA
Rodan
Sevgi B
SB
Duggan
Mark E
ME
Meissner
Robert S
RS
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
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D011760:Pyrrolidinones