Letters in Drug Design & Discovery - Volume 2, Issue 8, 2005

The new antihypertensive I1-receptor agonist (4) was rationally synthetized by the insertion of a phenyl group in the ortho position of the aromatic ring of the I1-selective antagonist (3). This "antagonismagonism" modulation, highlights the existence of expected analogies between I1- and α2-adrenoreceptor systems. Chirality proves to be crucial for the activation of I1-receptors, since the cardiovascular effects are produced exclusively by the (S)-(+)-4 enantiomer.

docking simulations were performed on the open and the closed conformations of (S)-adenosyl-Lhomocysteine- hydrolase with a series of L-adeninylalanine analogues. Theoretical Ki values were calculated and compared to experimental Ki's, determined after enzymatic assay. These results suggest that the competitive inhibitors evaluated bind reversibly to the open form of SAH-hydrolase and do not induce the conformational transition to the closed conformation.

Five polydentate ligands 2-6 were prepared from arylamines and precursors 1a-b. The polydentate (2-4) and (5) showed marked activity against cancer cell lines. The substituents (R and R') appear to play a key role in the cytotoxic potency of this class of compounds.

Surface plasmon resonance imaging, a low affinity screening method, allows the highly parallel detection of small molecules binding to a target protein. The screening of a fragment based compound library immobilized on chemical microarrays resulted in the discovery of binding fragments for the serine protease thrombin. Functional assays confirmed enzymatic inhibition of microarray hits and crystallography established the binding mode of a non-basic S1 motif providing a starting point for medicinal chemistry.

A privileged structure has been identified within the 1,300-member diversified library by rational selection of the compounds to be tested prior to the screening towards enzymatic β-secretase (BACE-1) assay. The identified hexahydrobenzothiazole privileged structure has been optimised and a preliminary structureactivity study has been performed.

In exploring for templates to devise novel antagonists for the integrins α4β1 and α4β7, was a series of compounds identified possessing a 1,2,4-triazolo[2,3-a]pyrrole structural subunit. Compound 11, for example, was found to antagonize α4β1-VCAM-1 and α4β7-MAdCAM-1 adhesion with IC50 values of 80 and 20 nM, respectively.

In this review we describe various applications of Szeged (Sz) index for modeling physicochemical properties as well as physiological activities of organic compounds acting as drugs or possess pharmacological activity.

Caprolactam urea 1, identified as a weak Factor Xa inhibitor screening hit (IC50 = 16 μM), served as the starting point for a limited parallel-synthesis driven SAR study to improve potency. Remarkably, the corresponding thiourea analog 8c (IC50 = 0.11 μM) was 145-fold more potent against Factor Xa compared to 1. In general, caprolactam analogs containing a thiourea linker were significantly more potent than their corresponding urea counterparts, and it is hypothesized that this is partly due to a conformational preference of the thiourea linkage which facilitates binding of the terminal groups of the inhibitors to the Factor Xa S1/S4 pockets. Analog 8c was selective against a panel of related serine proteases. Upon intra-duodenal administration in rats, 8c dose-dependently increased prothrombin time ex vivo, and when dosed i.v., it demonstrated efficacy in a rat model of venous thrombosis. This thiourea lead series formed the basis for follow-on investigations to discover potent drug-like Factor Xa inhibitors using the caprolactam scaffold but employing suitable thiourea surrogates.

Four new p-nitrophenyl β-D-glucuronide analogues, potentially useful as new triggers for β- glucuronidase mediated P.M.T. (Prodrug Mono-Therapy), have been prepared in a few steps. These compounds were tested for hydrolysis in the presence of either Escherichia Coli or bovine liver β-glucuronidase. The KM and Vmax values obtained for each analogue are reported.

The aspartic protease of HIV-1 represents a valid therapeutic target of antiviral agents suitable for the treatment of AIDS. We have designed peptidomimetic inhibitors for this enzyme with a hydroxyethylenediamine core, based on a molecular modeling approach that predicts the effectiveness of the designed compounds in terms of computed enzyme-inhibitor complexation Gibbs free energies. This structurebased molecular design was then combined with a synthetic strategy that couples stereochemical control with full flexibility in the choice of the central core side chains and of the flanking residues. A series of peptidomimetic inhibitors was thus assembled from readily available amino acids and carboxylic acids and -Phe-ψ[CH2-(r/s)CHOH]-Phe- cores. The IC50 values for these compounds ranged from 3 nM to 80 μM, allowing a QSAR analysis and identification of factors that determine the inhibition potency of the compounds. Predicted ADME-related properties of the inhibitor candidates span a range of pharmacokinetics profiles, which allows selection of a potent and bioavailable lead compound for further development.