Chiral heterocycles by iminium ion cyclization.

We present a new descriptor named signature based on extended valence sequence. The signature of an atom is a canonical representation of the atom's environment up to a predefined height h. The signature of a molecule is a vector of occurrence numbers of atomic signatures. Two QSAR and QSPR models based on signature are compared with models obtained using popular molecular 2D descriptors taken from a commercially available software (Molconn-Z). One set contains the inhibition concentration at 50% for 121 HIV-1 protease inhibitors, while the second set contains 12865 octanol/water partitioning coefficients (Log P). For both data sets, the models created by signature performed comparable to those from the commercially available descriptors in both correlating the data and in predicting test set values not used in the parametrization. While probing signature's QSAR and QSPR performances, we demonstrates that for any given molecule of diameter D, there is a molecular signature of height h </= D+1, from which any 2D descriptor can be computed. As a consequence of this finding any QSAR or QSPR involving 2D descriptors can be replaced with a relationship involving occurrence number of atomic signatures.

The signature molecular descriptor. 1. Using extended valence sequences in QSAR and QSPR studies.

The concept of signature as a molecular descriptor is introduced and various topological indices used in quantitative structure-activity relationships (QSARs) are expressed as functions of the new descriptor. The effectiveness of signature versus commonly used descriptors in QSAR analysis is demonstrated by correlating the activities of 121 HIV-1 protease inhibitors. Our approach to the inverse-QSAR problem consists of first finding the optimum sets of descriptor values best matching a target activity and then generating a focused library of candidate structures from the solution set of descriptor values. Both steps are facilitated by the use of signature.

Developing a methodology for an inverse quantitative structure-activity relationship using the signature molecular descriptor.

The invention relates to novel phenyl-substituted pyrazolopyrimidines, to a method for the production thereof, and to their use for producing medicaments serving to improve perception, concentration, learning and/or memory.

Phenyl-substituted pyrazolopyrimidines

Synthesis and biological activity of selective pipecolic acid-based TNF-α converting enzyme (TACE) inhibitors

Preparation of (2S,4R)-4-Hydroxypipecolic Acid and Derivatives

A novel series of pyrimidine derivatives was synthesized and evaluated for positive inotropic activity. Inotropic and chronotropic effects were determined in vitro in cat papillary muscle and right atrium, respectively. Selected compounds were then evaluated in vivo in a dog heart failure model. Changes in ventricular dP/dt, heart rate, and blood pressure were monitored. Several of these agents produced relatively minor changes in heart rate. This class of agents demonstrated a varying degree of vasodilator effects concomitant with increases in ventricular contractility. The most potent analogues, 9, 48, and 49, were evaluated orally in conscious dogs with implanted Konisberg pressure transducers, and their effect on left ventricular dP/dt was compared with that of milrinone. Mechanistically, the agents of this novel class appear not to mediate their effect via beta-receptors or inhibition of Na+/K+-ATPase. A major component of their inotropic effect is mediated by the inhibition of cardiac phosphodiesterase (PDE)-Fr. III. This was clearly demonstrated by 9, 48, and 49. Compound 48 was found to be the most potent inhibitor of PDE-Fr. III from among the compounds tested in this assay.

Chemistry and positive inotropic effect of pelrinone and related derivatives. A novel class of 2-methylpyrimidones as inotropic agents.

A series of HIV protease inhibitors containing a novel (hydroxyethyl)amidosuccinoyl core has been synthesized. These peptidomimetic structures inhibit viral protease activity at low nanomolar concentrations (IC50 < 10 nM for HIV-1 protease). The inhibition constant (Ki) for inhibitor 19 was determined to be 7.5 pM against HIV-1 and 1.2 nM against HIV-2 proteases, respectively. Several compounds (19−24) inhibited HIV-1 replication in cell culture assays with 50% effective concentrations (EC50) = 3.7−35 nM. This series of inhibitors was found to exhibit poor bioavailability (<10%) in the rat, following oral administration. The synthesis and biological properties of these compounds are discussed. In addition, an X-ray structure of one of these inhibitors (23) in complex with HIV-2 protease provides insight into the binding mode of this novel class of HIV protease inhibitors.

Potent HIV Protease Inhibitors Containing a Novel (Hydroxyethyl)amide Isostere

A photoannelation reaction between 2 alpha beta-unsaturated ketones is described. The photoadduct was isolated and characterized by spectral analysis and was transformed into methoxy and acetoxy derivatives. Some mechanistic implications of photoannelation and the finding of a rearrangement product are discussed. Transformations of diketone to other prostanoic acid derivatives are also described. Structural formulas are depicted in a stepwise manner.

Tibor Bogri

Papers

Preparation of (2S,4R)-4-Hydroxypipecolic Acid and Derivatives

Chemistry and positive inotropic effect of pelrinone and related derivatives. A novel class of 2-methylpyrimidones as inotropic agents.

Potent HIV Protease Inhibitors Containing a Novel (Hydroxyethyl)amide Isostere

Prostaglandins. IV. Total syntheses of dl-11-deoxy PGE 1 and 13,14-dihydro derivatives of 11-deoxy PGE 1 , PGF 1 , and PGF 1 .

Preparation of enantiopure 4-oxygenated pipecolic acid derivatives