Vitronectine receptor antagonist

Propanoic acid derivatives containing purine, (I), prepared by co-author Peyman (1) and 3-sulfanyl-3-pyridinyl, (II), prepared by Bandiera (2) were effective as vitronectin receptor antagonists and used in the treatment of bone resorption disorders. 

Figure 13 A labeled vitronectin receptor antagonist for tumor imaging...

Processes on pilot scale were reported by GlaxoSmithKline [74] for a subsituted itaconic acid for a vitronectine receptor antagonist (Scheme 30) and by Chemi [75] for the hydrogenation of a chlorinated p-keto ester depicted in Scheme 31 applied... 

Scheme 30 Synthesis of vitronectine receptor antagonist (GlaxoSmithKline)...

In 2004, a multikilogram-scale Heck coupling, using Pd(OAc)2/P(o-tolyl)3 catalytic system, was explored by Wallace et al. [14] at GlaxoSmithKline in their synthetic scheme of the vitronectin receptor antagonist 25. The key intermediate, frowvselective 24 was synthesized by Heck reaction between aryl bromide 22 and itaconic acid 23, using 1 mol% Pd(OAc)2,3 mol% P(o-tolyl)3, EtjN and -Bu NBr (Scheme 9.6). 

In addition to the well known examples of Ilb/IIIa, antagonists of other integrins like a P, (vitronectin receptor), rcP, a pg, fc,P, and a,P have been synthesised. The design of ot p receptor antagonists was based on... 

Integrin ayPs, the vitronectin receptor, has been identi-hed as a promising potential target for the treatment of osteoporosis, diabetic retinopathy and cancer. Three classes of integrin antagonists are currently in preclinical and clinical development monoclonal antibodies targeting the extracellular domain of the heterodimer, vitaxin, synthetic peptides such as cilengitide and several peptidomimetics. ... 

William H. Miller, Richard M. Keenan, Robert N. Willette, Michael W. Lark, Identification and in vivo efficacy of small-molecule antagonists of integrin a 3 (the vitronectin receptor), Drug Discovery Today, 5 (2000), 397-408. 

In another example of intermolecular Heck reaction shown below, 4-bromoindole was coupled with a BOC-protected 7-vinyl-1,2,3,4-tetrahydronaph-thyridine olefin in 63% yield. The resulting alkene was manipulated to a potent otv a antagonist, a vitronectin receptor that has been identified as a promising potential target for the treatment of osteoporosis, diabetic retinopathy, and cancer. 

Cycloalkyl alkanoic acids, (HI), prepared by Srinivasan (3) were effective as vitronectin v(33 and/or v(35 receptor integrin antagonists and used to decrease bone resorption and to restore the normal balance of bone forming/resorbing period. 

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