Nonpeptide alpha(v)beta(3) antagonists. 1. Transformation of a potent, integrin-selective alpha(IIb)beta(3) antagonist into a potent alpha(v)beta(3) antagonist.
Modification of the potent fibrinogen receptor (alpha(IIb)beta(3)) antagonist 1 generated compounds with high affinity for the vitronectin receptor alpha(v)beta(3). Sequential modification of the basic N-terminus of 1 led to the identification of the 5,6,7, 8-tetrahydro[1,8]naphthyridine moiety (THN) as a lipophilic, moderately basic N-terminus that provides molecules with excellent potency and selectivity for the integrin receptor alpha(v)beta(3). The THN-containing analogue 5 is a potent inhibitor of bone resorption in vitro and in vivo. In addition, the identification of a novel, nonpeptide radioligand with high affinity to alpha(v)beta(3) is also reported.
Duggan
M E
ME
Departments of Medicinal Chemistry, Bone Biology and Osteoporosis Research, and Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Duong
L T
LT
Fisher
J E
JE
Hamill
T G
TG
Hoffman
W F
WF
Huff
J R
JR
Ihle
N C
NC
Leu
C T
CT
Nagy
R M
RM
Perkins
J J
JJ
Rodan
S B
SB
Wesolowski
G
G
Whitman
D B
DB
Zartman
A E
AE
Rodan
G A
GA
Hartman
G D
GD
D000818:Animals; D001862:Bone Resorption / Q000473:pathology; D002460:Cell Line; D046508:Culture Techniques; D006801:Humans; D008024:Ligands; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C415162:2-benzenesulfonylamino-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)benzoylamino)propionic acid; D008024:Ligands; D009287:Naphthyridines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011422:Propionates; D013449:Sulfonamides