Drug Design Reviews - Online (Discontinued) - Volume 2, Issue 7, 2005

Angiotensin-converting enzyme (ACE) inhibitors effectively interfere with the renin-angiotensin system and exert various beneficial actions on cardiovascular system beyond their blood pressure-lowering effects. Controlled clinical trials have shown that ACE inhibitors improve endothelial function and vascular remodelling, and reduce the risk of myocardial infarction, stroke, and cardiovascular death. Data from experimental studies showed that ACE inhibitors can attenuate the development of atherosclerosis in a wide range of species. Further studies are needed to better understand pathophysiological mechanisms involved in vascular protection induced by ACE-inhibitors. ACE inhibitors have been used extensively in the management of patients with hypertension and heart failure. Over the past decade, a large body of evidence has emerged indicating that ACE inhibition also favorably affects the vasculature, and that these effects are associated with improved patient outcomes. Such evidence is provided by several sources: (i) experimental studies, which demonstrate that in addition to blood pressure lowering, ACE inhibitors improve endothelial function and have a host of other beneficial effects on the arterial wall; (ii) epidemiologic studies, which link the reninangiotensin- aldosterone system to increased risk for myocardial infarction, and (iii) clinical trials, which demonstrate that treatment with these agents reduces the risk for acute ischemic events, improves the function of the arterial endothelium and can retard the progression of the anatomic extent of atherosclerosis.

Angiotensin converting enzyme (ACE) inhibitors have a myocardial protective effect, especially against the ischemia/reperfusion injury induced during coronary artery bypass grafting (CABG). Indications, dose, suitable time, and duration of administration, however, are still controversial. The heart that has undergone CABG has many pathological features, such as infarction-associated hypertrophy, myocardial stunning, vulnerability to arrhythmias, and coronary artery dysfunction. Recent studies indicate a significant role for ACE and angiotensin II receptor polymorphisms in the reaction to heart surgery. In this review, we discuss role of ACE in each pathological condition. Unlike conventional CABG, the newer off-pump CABG technique does not require cooling of the heart, and we discuss the temperature dependency of ACE inhibitors. The optimal use of ACE inhibitors in clinical practice requires consideration of many factors.

Soft tissue sarcomas (STSs) belong to a rare, heterogeneous family of malignancies of mesenchymal origin. Inoperable or metastatic sarcomas typically show low responsiveness to conventional chemotherapy probably due to overexpression of several genes related to cell cycle control, cell maintenance, and DNA repair. The ecteinascidins (ETs) are potent and selective antitumor agents isolated from marine tunicades from the Caribbean, Ecteinascidia turbinate. Of the numerous ETs that have been isolated, ET-743 (Yondelis™, Trabectedin™) is the most promising compound for treatment of STSs. ET-743 is an alkaloid composed of three fused tetrahydroisoquinoline rings (A, B and C subunits) and is structurally related to the DNA-reactive saframycins. While the A and B subunits of ET-743 provide the scaffold for DNA recognition and binding, the C subunit makes only limited contacts with DNA. It has been proposed that ET-743 can also bind to the major endonucleases involved in base (BER) and nucleotide (NER) excision DNA repair, resulting in cytotoxic DNA-ET-743-protein ternary complexes. Interestingly, absence of the C subunit in the ET molecule results in distinct pharmacological activities when compared to ET-743 and could lead to the design of more potent and selective ET-derived drugs for STSs treatment.

Drug development for pediatric tumors is slow in comparison with efforts focused on adult cancers. Present risk-based therapy for neuroblastoma, the most common extra-cranial solid tumor in children, is usually effective in intermediate risk patients but treatment of the advanced disease in children over 2 years of age is not satisfactory. Novel targeted therapeutics that are at early stages of preclinical and clinical development for treatment of neuroblastoma include inhibitors of signal transduction and angiogenesis, stimulators of apoptosis/differentiation, and immunotherapeutics. That diverse panel of small molecules and biologics is often characterized by improved therapeutic indices in comparison with conventional agents and holds promise for the treatment and prevention of neuroblastoma

In the last decade, several efforts have been made to comprehend the molecular basis of hypertension through the study of Angiotensin II antagonists (AT1 antagonists or class of SARTANs since they share the same suffix in their empirical name). The structural features which determine the pharmacophoric segments of SARTANs are examined using a combination of QSAR and conformational analysis. The final scope of these studies is the prediction of the drug-receptor interactions. Many efforts dedicated to site directed mutagenesis on the human AT1 receptor have identified binding regions for non peptide antagonists. Lack of x-Ray data for the AT1 receptor enforces researchers to use computational methods in order to model it. Recent homology based models of the AT1 receptor have been built on the crystal structure of the bovine rhodopsin. Computer programs dedicated to docking small molecules into protein binding pockets in silico are currently applied. This review article demonstrates the determination of a possible active site of the receptor merging data from biophysical and mutational studies as well as theoretical calculations using SiteID (SYBYL) software. In particular, results show that the site of action for non peptide AT1 antagonists includes aminoacids such as Lys199, Val108 and His256 located at the mesophase of lipid bilayers. Such topography of these key aminoacids has been proposed to be the location of AT1 antagonists using biophysical techniques. The obtained data support the two step mechanism of action proposed in our previous studies. Manual placement of the classic AT1 antagonist, losartan in the pocket using its low energy conformation as determined elsewhere through a combination of NMR and molecular modeling techniques show its suitable fit characterized by energy favored multiple contacts.

Tumor cell targeting is a promising drug delivery strategy. Folate receptor (FR) is a cellular marker selectively overexpressed in a significant fraction of human neoplasms. Folate derivatized liposomes loaded with therapeutic agents have been shown to be efficiently taken up and to exhibit selective cytotoxicity in receptor positive tumor cells. FRtargeted liposomes have thus been evaluated for the targeted delivery of a variety of bioactive agents, including chemotherapeutic agents, antisense oligos, plasmid DNA, photosensitizers, and neutron capture agents. In addition, FRtargeted liposomal anthracyclines have been shown to overcome Pgp-mediated drug resistance in vitro and to have superior antitumor activity to non-targeted control liposomes in several preclinical murine solid tumor as well as leukemia models. Furthermore, strategies have been developed to selectively upregulate FR expression in tumor cells, which might further enhance the translational potential of this targeting strategy. The small size and presumed lack of immunogenicity of folate as a targeting ligand make these liposomes particularly attractive candidates for future clinical development.