Antagonist therapeutic uses

A bioxantracene (-)-ES-242-4 (46) was isolated from the culture broth of Verticillium sp. in 1992 as one of eight antagonists for the 7V-methy 1-D-aspartate (NMDA) receptor (7<5). These novel natural products are reported to inhibit the PH]thienyl cyclohexylpiperidine binding to rat crude synaptic membranes, and therefore, are of potential therapeutic interest for die treatment of neurodegenerative diseases. (-)-ES-242-4 (46) is structurally remarkable having an axially chiral binaphthalene core that is adorned with two pyrans of the same absolute chirality. Our interest in the construction of densely functionalized naphthopyran ring systems, via tandem Michael-Dieckmann reactions, promoted us to attempt the first stereocontrolled total synthesis of (-)-ES-242-4 (46) (19). 

We felt the best hope for creating the optimal drug and treatment regiment would be obtained by understanding what was happening to cells upon the introduction of the IAP antagonist. We reasoned that such information should help us identify biomarkers and allow us to make evidence based decisions on when and how to use IAP antagonist based therapeutics. 

Current limitations in the therapeutic use of MAbs are derived from the fact that they are pathogen-specific and that, for the time being, they require systemic, parenteral, and sometimes chronic application. In addition, antagonistic principles require rather large doses in excess of 1 mg kg body weight and this results in treatment costs of up to US 10000 per patient and therapy. For example, Avastin treatment is priced at US 4400 per month. 

Most calcium antagonists do not affect intraventricular conduction, so the QRS duration is usually unaffected. The PR interval may be prolonged even with therapeutic doses of verapamil. Bepridil prolongs the QT interval and may cause ventricular arrhythmias, including torsade de pointes (see p 14). Mibefradil also causes QT prolongation, and has been associated with ventricular arrhythmias. It has been removed from the US market. 

Valsartan (1, (5)-3-methyl-2-[V-( 4-[2-(2//-l,2,3,4-tetrazol-5-yl) phenyl]phenyl methyl)pentanamido]butanoic acid, generic name Diovan , Novartis) is a representative of a therapeutic class of non-peptidic angiotensin ll-(ATl) receptor antagonists, the sartans, developed for the treatment of hypertension. With US 4.2 billion global sales, valsartan holds the largest hypertension market share [1]. 

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