Nonpeptide α_vβ₃ Antagonists. 1. Transformation of a Potent, Integrin-Selective α_IIbβ₃ Antagonist into a Potent α_vβ₃ Antagonist

Abstract

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.

High-Affinity αvβ3 Integrin Targeted Optical Probe as a New Imaging Biomarker for Early Atherosclerosis: Initial Studies in Watanabe Rabbits

“…data) was synthesized as previously described. Briefly, ITOP was developed from a potent fibrinogen receptor antagonist (3-amino-2(S)-arylsulfonylaminopropionic acid derivative) [20] with further structural modifications, followed by conjugation to FITC. The conjugation of the fluorophore to the integrin antagonist did not alter the binding affinity or selectivity to integrin αvβ3.…”

Convergent, parallel synthesis of a series of β-substituted 1,2,4-oxadiazole butanoic acids as potent and selective αvβ3 receptor antagonists

“…11 The 1,8-tetrahydronaphthyridine moiety was incorporated, which was known to be an effective guanidine mimetic when applied to a v b 3 antagonists. 12 Reaction of the hydroxyamidine 1 with 3-substituted or 3,3-disubstituted glutaric anhydrides 2 allowed construction of the 1,2,4-oxadiazole ring with concomitant introduction of a substituted butanoic acid chain (Scheme 1). 13 This allowed for the rapid parallel synthesis of a series of analogs in racemic form.…”

“…The 1,8-tetrahydronaphthyridine moiety was clearly an effective guanidine mimetic for these oxadiazole based a v b 3 antagonists, which is in line with the findings of other researchers. 12 Some structural variation of this part of the molecule was investigated however to determine if further optimization were possible. A selection of guanidine mimetic variants is shown in Table 3.…”

Synthesis and Biological Investigation of Novel Tricyclic Benzodiazepinedione-Based RGD Analogues

“…[15,16] Furthermore, a v b 3 antagonists may have potential use in the suppression of proliferative diabetic retinopathy, which causes blindness in diabetic patients, [17,18] and they may also be useful for the treatment of osteoclast-mediated osteoporosis. [19] It has been demonstrated that blocking of a v b 3 by a synthetic peptide mimetic diminished osteoclastic bone resorption in vitro and in vivo. [20±22] 1,3-bis-tert-butoxycarbonyl-2-methyl-2-thiopseudourea was carried out to obtain derivative 20.…”