Biomedical subjects
Publications and source records attributed to Dennis J Hlasta.
A series of pyrrolopyridine-substituted oxazolidinones containing various C-5 acetamide isosteres was synthesized and the structure-antibacterial activity relationships determined against a representative panel of susceptible and resistant Gram-positive bacteria.
A novel series of pyridazinone-functionalized phenylalanine analogues was prepared and evaluated for inhibition of cellular adhesion mediated by alpha4beta1/VCAM-1 and alpha4beta7/MAdCAM-1 interactions. Concise syntheses were developed and applied for exploration of structure-activity relationships pertaining to the pyridazinone ring as well as the N-acyl phenylalanine scaffold. Potent dual antagonists of alpha4beta1 and alpha4beta7 were generated from an amide subseries; antagonists selective for alpha4beta7 were identified from urea and carbamate-based subseries. The pharmacokinetic properties of selected members of the series have been determined in rats and demonstrate that the use of ester prodrugs and alterations to the amide linkage can lead to improved oral bioavailability in this series. An alpha4beta7-selective member of the carbamate subseries (36c), upon oral administration, demonstrated in vivo efficacy in the mouse DSS colitis model.
[reaction: see text] A regioselective method for the preparation of 1,5-trisubstituted 1H-1,2,3-triazoles via a 1,3-dipolar cycloaddition of 1-trimethylsilylacetylenes with organoazides is described. Immobilization of the azide on REM resin and subsequent cycloaddition afforded a 2 x 2 x 4 x 3 membered 1,5-disubstituted 1H-1,2,3-triazole library with an average purified yield of 68%.
Two parallel synthetic methods were developed to explore the structure-activity relationships (SAR) of a series of potent opioid agonists. This series of tropanylidene benzamides proved extremely tolerant of structural variation while maintaining excellent opioid activity. Evaluation of several representative compounds from this series in the mouse hot plate test revealed potent antinociceptive effects upon oral administration.
[reaction: see text] The addition of azido trimethylsilane to arylnitrileboronate esters is shown to proceed rapidly in dimethoxyethane to give aryltetrazoleboronate esters in moderate to good yields, with dibutyltin oxide as catalyst.
A new series of antibacterial ketolides is reported, which features the use of a C-6 carbamate for tethering the arylalkyl sidechain to the macrolide core. The best members of this series display in vitro and in vivo activity comparable to telithromycin. Partial epimerization at C-2, unobserved in previously reported ketolides, was noted for this series.
A novel series of 3,5-diarylisoxazole and 3,5-diaryl-1,2,4-oxadiazole IL-8 inhibitors has been identified. These compounds exhibit activity in an IL-8 binding assay as well as in a functional assay of IL-8 induced elastase release from neutrophils. In addition, one of the compounds exhibits oral activity in a rat adjuvant arthritis model.
Vasopressin receptor antagonists can elicit ion-sparing diuretic effects (i.e., aquaresis) in vivo by blunting the action of the circulating hypophyseal hormone arginine vasopressin. We have identified two new series of basic tricyclic benzodiazepines, represented by general structure 1, which contain compounds that bind with high affinity to human V2 receptors. For example, (S)-(+)-8 and 5 are potent and selective V2 receptor antagonists with pronounced aquaretic activity in rats on oral administration.
The design, synthesis, and biological activity of novel alpha(4)beta(1) and alpha(4)beta(7) integrin antagonists, containing a bridged azabicyclic nucleus, are reported. Conformational analysis of targets containing an azabicyclo[2.2.2]octane carboxylic acid and known integrin antagonists indicated that this azabicycle would be a suitable molecular scaffold. Variation of substituents on the pendant arylsulfonamide and phenylalanine groups resulted in potent alpha(4)beta(1)-selective and dual alpha(4)beta(1)/alpha(4)beta(7) antagonists. Potent compounds 11i, 11h, and 14 were effective in the antigen-sensitized sheep model of asthma.
A novel series of oxazolidinones containing a pyrroloaryl substituent was synthesized and screened against a representative panel of susceptible and resistant Gram-positive bacteria. Several members of this series were found to have antibacterial activity comparable to or better than linezolid.
The design and synthesis of novel pyrrolidine-containing bradykinin antagonists, II, are described. Conformational analysis suggested that a pyrrolidine moiety could substitute for the N-methyl cis-amide moiety of FR 173657. The in vitro binding data showed that the (S)-isomer of II was potent in the bradykinin B(2) receptor-binding assay with a K(i) of 33 nM. The opposite isomer, (R)-II, had a K(i) of 46 nM. The in vitro binding data confirmed our conformational hypothesis.
A new class of higher-boiling solvents was investigated for elevated-temperature solid-phase parallel synthesis. Extremely low vapor pressures at high temperature and a broader range of solvent effect tuning make this new class of solvents an ideal choice for high-temperature parallel solid-phase synthesis. Benzyl benzoate is identified as a superior high-boiling solvent for parallel solid-phase Lawesson's thionation reactions.
A new approach for the preparation of 2-substituted azole libraries using a polystyrene-carbamyl chloride resin in a traceless fashion is described. Azole substrates II are assembled in a one-pot condensation reaction of azoles and aldehydes with a resin-bound carbamyl chloride. Treatment of the azolyl-carbamate II with boron trifluoride etherate under thermal or microwave-assisted solvolysis conditions afforded 2-substituted azoles. [reaction: see text]
The synthesis and biological testing of a novel series of nonpeptide vasopressin receptor antagonists, containing a bridged bicyclic nucleus, are reported. Variation of substituents (R(1)-R(3)) in general formula 3, and the configuration of the stereocenter, resulted in potent V(2)-selective (e.g., 5) and balanced dual V(1a)/V(2) (e.g., 10) compounds. Data from receptor binding, cell-based functional, and in vivo assays are presented [corrected]
Oxazolidinone antibacterial agents, where the morpholino group of linezolid was replaced with an N-substituted piperidinyloxy moiety, were synthesized and shown to be active against a variety of resistant and susceptible Gram-positive organisms. The functionality attached to the piperidine nitrogen was varied extensively to determine the SAR for this series. One of the most potent compounds, 11, showed in vivo efficacy upon subcutaneous administration in a Staphylococcus aureus Smith murine systemic infection.
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