Publications by authors named "Andrzej Kieltyka"

The design, synthesis, and structure-activity relationships of a novel series of pyrazines, acting as corticotropin releasing factor-1 (CRF-1) receptor antagonists, are described. Synthetic methodologies were developed to prepare a number of substituted pyrazine cores utilizing regioselective halogenation and chemoselective derivatization. Noteworthy, an efficient 5-step synthesis was developed for the lead compound 59 (NGD 98-2), which required no chromatography.

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The complement system represents an innate immune mechanism of host defense that has three effector arms, the C3a receptor, the C5a receptor (C5aR), and the membrane attack complex. Because of its inflammatory and immune-enhancing properties, the biological activity of C5a and its classical receptor have been widely studied. Because specific antagonism of the C5aR could have therapeutic benefit without affecting the protective immune response, the C5aR continues to be a promising target for pharmaceutical research.

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A series of novel 1H-pyrazolo-[3,4-c]cyclophepta[1,2-c]thiophenes was prepared and screened at selected dopamine receptor subtypes. Compound 4 (NGB 4420) displayed high affinity and selectivity (>100-fold) for the D(4) over D(2) and other CNS receptors. This compound was identified as a D(4) antagonist via its attenuation of dopamine agonist-induced GTPgamma(35)S binding at D(4) receptor.

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The discovery, synthesis and structure-activity studies of a novel series of 2-arylpyrimidin-4-ones as CRF-1 receptor antagonists is described. These compounds are structurally simple and display appropriate physical properties for CNS agents

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5-piperazinyl-1,2,6,7-tetrahydro-5H-azepino[3,2,1-hi]indol-4-one derivatives were designed, synthesized, and identified as a new series of mixed dopamine D(2)/D(4) receptor antagonists. This series featured a rigid tricyclic ring system as an important pharmacophore core structure for high binding affinity. Molecular modeling studies are also described.

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A series of chiral benzylpiperazinyl-1-(2,3-dihydro-indol-1-yl)ethanone derivatives were prepared and examined for their affinity at dopamine D(2) and D(4) receptors. Three compounds having D(2)/D(4) affinity ratios approximating that found for the atypical neuroleptic clozapine were further evaluated in behavioral tests of antipsychotic efficacy and motor side effects.

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Optimization of the lead compound 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2,3-dihydro-indol-1-yl)-ethanone 1 by systematic structure-activity relation (SAR) studies lead to two potent compounds 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2-methy-2,3-dihydro-indol-1-yl)-ethanone 2n and 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2-methy-2,3-dihydro-indol-1-yl)-ethanone 7b. Their related synthesis was also reported.

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The synthesis of a series of 3-aryl pyrazolo[4,3-d]pyrimidines as potential corticotropin-releasing factor (CRF-1) antagonists is described. The effects of substitution on the aromatic ring, the amino group and the pyrazolo ring on CRF-1 receptor binding were investigated.

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