Dopamine receptor modulation by a highly rigid spiro bicyclic peptidomimetic of Pro-Leu-Gly-NH2.

A peptidomimetic analogue of Pro-Leu-Gly-NH2 (PLG), compound 3, has been synthesized that contains a highly constrained spiro bicyclic type-II beta-turn mimic. Peptidomimetic 3 enhanced the binding of the dopamine receptor agonist ADTN to dopamine receptors by 40% at 10(-6) M. At this same concentration PLG enhanced the binding of ADTN by 26%. Like PLG, 3 exhibited a bell-shaped dose-response curve with the maximum effect occurring at a concentration of 10(-6) M. Because of the highly rigid nature of the spiro bicyclic type-II beta-turn constraint found in 3, these results lend strong support for the hypothesis that the biologically active conformation of PLG is a type-II beta-turn.

Novel 1,5-diphenylpyrazole nonnucleoside HIV-1 reverse transcriptase inhibitors with enhanced activity versus the delavirdine-resistant P236L mutant: lead identification and SAR of 3- and 4-substituted derivatives.

Through computationally directed broad screening, a novel 1, 5-diphenylpyrazole (DPP) class of HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been discovered. Compound 2 (PNU-32945) was found to have good activity versus wild-type (IC(50) = 2.3 microM) and delavirdine-resistant P236L (IC(50) = 1.1 microM) reverse transcriptase (RT). Also, PNU-32945 has an ED(50) for inhibition of viral replication in cell cultures of 0.1 microM and was shown to be noncytotoxic with a CC(50) > 10 microM. Structure-activity relationship studies on the 3- and 4-positions of PNU-32945 led to interesting selectivity and activity within the class. In particular, the 3-hydroxyethyl-4-ethyl congener 29 is a potent inhibitor of the P236L mutant (IC(50) = 0.65 microM), whereas it is essentially inactive versus the wild-type enzyme (IC(50) > 50 microM). Furthermore, this compound was significantly more active versus the P236L mutant than delavirdine. The synthesis and RT inhibitory activity of various 3- and 4-substituted analogues are discussed.

Synthesis and structure-activity relationships of the (alkylamino)piperidine-containing BHAP class of non-nucleoside reverse transcriptase inhibitors: effect of 3-alkylpyridine ring substitution.

Development of resistance to currently approved HIV therapies has continued to fuel research efforts to improve the metabolic stability and spectrum of activity of the (alkylamino)piperidine-containing bis(heteroaryl)piperazine (AAP-BHAP) class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis of analogues in which the usual 3-alkylamino substituent on the pyridine ring is replaced by a 3-alkyl substituent led to compounds which retained activity against recombinant P236L and wild-type (WT) reverse transcriptase (RT), while inhibition of the Y181C mutant RT was reduced relative to the activity of the 3-alkylamino-substituted congeners. Testing of representative analogues in an in vitro liver microsome assay indicated that the alkyl substituent would not appreciably improve the metabolic stability of the AAP-BHAP template. In vivo pharmacokinetic evaluation of three compounds confirmed these results in that high systemic clearances were observed. Nevertheless, one compound (13), PNU-103657, possessed oral bioavailability in rats approaching that of the structurally related NNRTI drug delavirdine which is currently on the market for the treatment of HIV infection.

Synthesis and bioactivity of novel bis(heteroaryl)piperazine (BHAP) reverse transcriptase inhibitors: structure-activity relationships and increased metabolic stability of novel substituted pyridine analogs.

The major route of metabolism of the bis(heteroaryl)piperazine (BHAP) class of reverse transcriptase inhibitors (RTIs), atevirdine and delavirdine, is via oxidative N-dealkylation of the 3-ethyl- or 3-isopropylamino substituent on the pyridine ring. This metabolic pathway is also the predominant mode of metabolism of (alkylamino)piperidine BHAP analogs (AAP-BHAPs), compounds wherein a 4-(alkylamino)piperidine replaces the piperazine ring of the BHAPs. The novel AAP-BHAPs possess the ability to inhibit non-nucleoside reverse transcriptase inhibitor (NNRTI) resistant recombinant HIV-1 RT and NNRTI resistant variants of HIV-1. This report describes an approach to preventing this degradation which involves the replacement of the 3-ethyl- or 3-isopropylamino substituent with either a 3-tert-butylamino substituent or a 3-alkoxy substituent. The synthesis, bioactivity and metabolic stability of these analogs is described. The majority of analogs retain inhibitory activities in enzyme and cell culture assays. In general, a 3-ethoxy or 3-isopropoxy substituent on the pyridine ring, as in compounds 10, 20, or 21, resulted in enhanced stabilities. The 3-tert-butylamino substituent was somewhat beneficial in the AAP-BHAP series of analogs, but did not exert a significant effect in the BHAP series. Lastly, the nature of the indole substitution sometimes plays a significant role in metabolic stability, particularly in the BHAP series of analogs.

Substituent effects on the antibacterial activity of nitrogen-carbon-linked (azolylphenyl)oxazolidinones with expanded activity against the fastidious gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis.

A series of new nitrogen-carbon-linked (azolylphenyl)oxazolidinone antibacterial agents has been prepared in an effort to expand the spectrum of activity of this class of antibiotics to include Gram-negative organisms. Pyrrole, pyrazole, imidazole, triazole, and tetrazole moieties have been used to replace the morpholine ring of linezolid (2). These changes resulted in the preparation of compounds with good activity against the fastidious Gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis. The unsubstituted pyrrolyl analogue 3 and the 1H-1,2,3-triazolyl analogue 6 have MICs against H. influenzae = 4 microgram/mL and M. catarrhalis = 2 microgram/mL. Various substituents were also placed on the azole moieties in order to study their effects on antibacterial activity in vitro and in vivo. Interesting differences in activity were observed for many analogues that cannot be rationalized solely on the basis of sterics and position/number of nitrogen atoms in the azole ring. Differences in activity rely strongly on subtle changes in the electronic character of the overall azole systems. Aldehyde, aldoxime, and cyano azoles generally led to dramatic improvements in activity against both Gram-positive and Gram-negative bacteria relative to unsubstituted counterparts. However, amide, ester, amino, hydroxy, alkoxy, and alkyl substituents resulted in no improvement or a loss in antibacterial activity. The placement of a cyano moiety on the azole often generates analogues with interesting antibacterial activity in vitro and in vivo. In particular, the 3-cyanopyrrole, 4-cyanopyrazole, and 4-cyano-1H-1,2,3-triazole congeners 28, 50, and 90 had S. aureus MICs

Carbon-carbon-linked (pyrazolylphenyl)oxazolidinones with antibacterial activity against multiple drug resistant gram-positive and fastidious gram-negative bacteria.

In an effort to expand the spectrum of activity of the oxazolidinone class of antibacterial agents to include Gram-negative bacteria, a series of new carbon-carbon linked pyrazolylphenyl analogues has been prepared. The alpha-N-substituted methyl pyrazole (10alpha) in the C3-linked series exhibited very good Gram-positive activity with MICs