Discovery of a potent, dual serotonin and norepinephrine reuptake inhibitor.

The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior.

Investigation of retention behavior of drug molecules in supercritical fluid chromatography using linear solvation energy relationships.

In this study, the retention behaviors of pharmaceutical and drug-like compounds in supercritical fluid chromatography (SFC) with polar stationary phases were evaluated using linear solvation energy relationships (LSERs). We used more than 200 compounds, including mono-, di-substituted benzenes, and other marketed drugs with a wide range of solvation descriptors. The dominant contribution to positive retention was the hydrogen bond donor acidity of the solutes, particularly for pyridine and amino columns.

Analytical and biological evaluation of high throughput screen actives using evaporative light scattering, chemiluminescent nitrogen detection, and accurate mass LC-MS-MS.

In this investigation the utility of evaporative light scattering detection (ELSD) combined with HPLC-MS was demonstrated as a key component of a bioassay-guided fractionation, or "biofractionation" technique, for the evaluation of high throughput screen actives. ELSD provided on-line analyte mass information that was critical for the classification of the samples. Chemiluminescent nitrogen detection (CLND) was also evaluated for sample concentration estimation for nitrogen-containing compounds, and accurate mass LC-MS-MS analysis was employed for rapid structural confirmation and elucidation of components previously identified as active via biofractionation.

Medicinal chemistry in the development of societies. Biodiversity and natural products.

This document has been elaborated by the IUPAC Medicinal Chemistry section and is backed by a large number of scientists, many of whom have had direct involvement and whose names appear at the end of the article. This work discusses the role that the discovery of new medicinal agents has in the development of societies as well as in the conservation of biodiversity in terms of work carried out on natural products. Also included are several recommendations for countries which are presently in search of their own scientific and technological development in medicinal agents.

Novel naphthoquinones from a Streptomyces sp.

Cdc25A assay-guided fractionation of a fermentation broth derived from a Streptomyces sp. resulted in the isolation of four novel naphthoquinones 1-4. Structures of these compounds were deduced by NMR and mass spectrometry.

The nanometer-scale structure of amyloid-beta visualized by atomic force microscopy.

Amyloid-beta (A beta) is the major protein component of neuritic plaques found in Alzheimer's disease. Evidence suggests that the physical aggregation state of A beta directly influences neurotoxicity and specific cellular biochemical events. Atomic force microscopy (AFM) is used to investigate the three-dimensional structure of aggregated A beta and characterize aggregate/fibril size, structure, and distribution.

Dimensionality in optical fields and signals.

The spatial chaos in optical fields that result from diffraction of plane waves by random-phase objects with a larger-than-unity phase dispersion is studied. An analog method for evaluating the dimension of chaos in the field is described, and a real-time measuring device that uses this method is proposed. A new method for evaluating the signal-to-noise ratios in optical signals is also proposed.

Optical correlation method for measuring spatial complexity in optical fields.

An analog method for measuring spatial complexity in optical fields generated by randomly phased objects is proposed. The method is used to make a device for high-speed real-time optical field measurements.

A83016F, a new member of the aurodox family.

A new member of the aurodox family of antibiotics, A83016F, has been isolated from an unidentified actionmycete designated A83016. The structure and relative stereochemistry of A83016F were elucidated by NMR examination of the parent compound and its diacetate derivative. A83016F exhibits only weak antimicrobial activity.

Bioactive compounds from aquatic and terrestrial sources.

The world of nature provides a never-ending set of fascinating problems for the chemist. Many of the most intriguing problems, however, concern compounds available in only truly minute quantities. One solution is to focus on bioassay-guided separations.

New inhibitors of renin that contain novel phosphostatine Leu-Val replacements.

A novel series of renin inhibitors based on the Phe8-His9-Leu10-Val11 substructure of renin's natural substrate, angiotensinogen, is reported. These inhibitors retain the Phe8-His9 portion of the native substructure and employ novel phosphostatine Leu10-Val11 replacements (LVRs). The phosphostatine LVRs were prepared by condensing a dialkyl phosphonate ester stabilized anion with either N-t-Boc-amino aldehydes or N-tritylamino aldehydes (derived from the corresponding amino acid).

Cardiovascular actions of the primate-selective renin inhibitor, A-62198.

A-62198 [dimethylacetyl-Phe-His-NHCH(cyclohexylmethyl)CH-(OH)C H(OH)CH2N3] is a potent, selective inhibitor of primate renin. This compound induced a dose-dependent fall in mean arterial blood pressure (MAP) when administered as an i.v.

Effects of the renin inhibitor A-64662 in monkeys and rats with varying baseline plasma renin activity.

The efficacy of the potent, primate selective renin inhibitor A-64662 was studied in monkeys and rats with varying baseline plasma renin activity (PRA) to elucidate the relationship between PRA and the hypotensive response induced by this compound. The effect of a single bolus of vehicle or A-64662 at 0.001, 0.

Renin inhibitors. Improvements in the stability and biological activity of small peptides containing novel Leu-Val replacements.

We have designed a novel class of potent (0.3-7 nM) renin inhibitors which contain a dihydroxyethylene replacement for what is formally the Leu10-Val11 amide bond. Good potency (0.

New inhibitors of human renin that contain novel Leu-Val replacements. Examination of the P1 site.

Stereoselective syntheses of several nonpeptide sulfidoethanol fragments that function as Leu10-Val11 (P1-P1') scissile bond replacements in human angiotensinogen are presented. These fragments are prepared from a variety of amino acids with formal P1 side chains varying in size and lipophilicity by converting them to their corresponding N-protected aminoalkyl epoxide 5 followed by ring opening with isopropyl mercaptan. The coupling of these fragments to either Boc-Phe-Ala-OH or Boc-Phe-His-OH produces inhibitors of human renin, 6 and 7, respectively, which are compared to a series of dipeptide-aldehyde inhibitors, 4, by molecular modeling and biochemical methods.

Renin inhibitors. Dipeptide analogues of angiotensinogen incorporating transition-state, nonpeptidic replacements at the scissile bond.

A series of dipeptide analogues of angiotensinogen have been prepared and evaluated for their ability to inhibit the aspartic proteinase renin. The compounds were derived from the renin substrate by replacing the scissile amide bond with a transition-state mimic and by incorporating bioisosteric replacements for the Val-10 amide bond. Analogue 21a exhibited an IC50 of 7.

New inhibitors of human renin that contain novel Leu-Val replacements.

Stereoselective syntheses of several nonpeptide fragments that function as Leu10-Val11 scissile bond replacements in human angiotensinogen are presented. The opening of N-protected aminoalkyl epoxide 3 with a variety of sulfur, oxygen, nitrogen, and carbon nucleophiles is a key reaction in the preparation of these novel fragments 4-8. The coupling of these fragments to protected dipeptides that mimic positions 8 and 9 in angiotensinogen produces inhibitors of human renin even though the molecules contain no functionality beyond what is formally the Val11 side chain of angiotensinogen.

Novel renin inhibitors containing analogues of statine retro-inverted at the C-termini: specificity at the P2 histidine site.

Substituted 1,3- and 1,4-diamines were prepared from epoxides derived from Boc-leucine or Boc-cyclohexylalanine. These diamines were incorporated into renin inhibitors (IC50 = 4-1500 nM) replacing the Leu-Val scissile bond in small peptide analogues of angiotensinogen. Replacement of the P2 histidine imidazole with other heterocycles maintained or enhanced binding while changing the overall basicity of the inhibitor.

Modified peptides which display potent and specific inhibition of human renin.

A new class of angiotensinogen analogues which contain heteroatom-methylene and retro-inverso amide bond replacements was synthesized and evaluated for renin inhibition. Selected compounds in the series were specific for renin over other aspartic proteinases, and the most potent inhibitor demonstrated hypotensive activity in a salt depleted monkey.

Peptide analogues of angiotensinogen. Effect of peptide chain length on renin inhibition.

Renin inhibition was evaluated for a series of peptide analogues of angiotensinogen with different chain lengths. Systematic deletion of amino acid residues from the hexapeptide BocPheHisLeuR-ValIleHisOCH3 showed that the presence of residues at the N-terminal Phe and His positions was essential for efficient enzyme-inhibitor binding whereas the C-terminal Ile and His residues were much less important. Synthesis of a tetrapeptide analogue shortened at the C-terminus and containing modified side chains produced a potent inhibitor of renin which demonstrated hypotensive activity in a salt depleted monkey.

Two-dimensional 1H NMR studies of rat atrial natriuretic factor(1-23).

Using a variety of two-dimensional NMR methods, the 1H NMR resonances of rat ANF(1-23) in dimethyl sulfoxide-d6 solution have been assigned. Two-dimensional phase sensitive correlated spectroscopy was used to identify protons that are scalar coupled and were also used to obtain coupling constants (3JNH-alpha CH) in complicated regions of the spectra. Relayed coherence transfer experiments proved useful in identifying the connectivities between the NH and beta-protons of the same amino acid residue.

Preparation of biologically active ristocetin derivatives: replacements of the 1'-amino group.

A series of ristocetin analogues with modifications (OH, C=O, C=NOH, NCOCH3) at the C-1' amino group was synthesized and found to possess antibacterial activity against gram-positive bacteria and to bind to Ac2-Lys-D-Ala-D-Ala, a model for the antibiotic's site of action. Due to the lack of a positively charged amino group, the active analogues could not form a salt bridge, indicating that an electrostatic interaction between the positively charged 1'-amino group of ristocetin and the carboxylate anion of the peptide is not required for complex formation. The only compound that did not exhibit good antibacterial activity was epiristocetin aglycone (an analogue with the 1'amino group in the opposite configuration (S) as ristocetin).

Semi-automated preparation of a 11C-labelled antibiotic--[N-methyl-11C]erythromycin A lactobionate.

A fast semi-automated method is described for labeling the antibiotic, erythromycin A (1), with the short-lived positron-emitting radionuclide, 11C (t 1/2 = 20.4 min), in order to permit the non-invasive study of its tissue uptake in vivo. Labelling was achieved by the fast reductive methylation of N-demethylerythromycin A (2) with [11C]formaldehyde, itself prepared from cyclotron-produced [11C]-carbon dioxide.