Synthesis and anti-HIV activities of urea-PETT analogs belonging to a new class of potent non-nucleoside HIV-1 reverse transcriptase inhibitors

A series of potent specific HIV-1 RT inhibitory compounds is described. The compounds are urea analogs of PETT (PhenylEthylThiazoleThiourea) derivatives and the series includes derivatives with an ethyl linker (1-6) and conformationally restricted analogs (7-13). The antiviral activity is determined both at the RT level and in cell culture on both native and mutant forms of HIV-1. Many compounds display activity in the nM range against wt-RT.     

N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-2-nitroaniline, a potent muscarinic agonist

The muscarine receptor agonist SK-946, an aniline derivative with a characteristic bicyclo amine, was found. We describe a new synthetic method for 1-azabicyclo[3.3.0]octane and describe the biological activity of SK-946.     

Nonlinear pharmacokinetics of efavirenz (DMP-266), a potent HIV-1 reverse transcriptase inhibitor, in rats and monkeys

PURPOSE: Our purpose was to evaluate the L-ascorbate level in human preovulatory follicular fluid and to quantify the blood/follicle gradient for vitamin C. The effect of smoking on the follicular L-ascorbate concentration was studied. The correlations were tested between follicular L-ascorbate and follicle size and oocyte maturity. METHODS: In 65 women undergoing in vitro fertilization, samples of follicular fluid and blood serum were collected. Biochemical analyses included L-ascorbate determinations by a colorimetric method and cotinine measurements by a radioimmunoassay. RESULTS: The average follicular fluid:serum ratio for L-ascorbate was 1:68. Ascorbate levels in follicular fluid and serum were significantly correlated. The follicular L-ascorbate level did not correlate with the follicle size and the oocyte maturity grade. Insignificantly lowered follicular L-ascorbate levels were observed in smokers. CONCLUSIONS: The extracellular compartment of the Graafian follicle is a site of an ascorbate accumulation. Exposure to tobacco smoke does not significantly diminish the intrafollicular pool of L-ascorbate.     

Phenethylthiazolylthiourea (PETT) compounds as a new class of HIV-1 reverse transcriptase inhibitors. 2. Synthesis and further structure-activity relationship studies of PETT analogs

Phenylethylthiazolylthiourea (PETT) derivatives have been identified as a new series of non-nucleoside inhibitors of HIV-1 RT. Structure-activity relationship studies of this class of compounds resulted in the identification of N-[2-(2-pyridyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea hydrochloride (trovirdine; LY300046.HCl) as a highly potent anti-HIV-1 agent. Trovirdine is currently in phase one clinical trials for potential use in the treatment of AIDS. Extension of these structure-activity relationship studies to identify additional compounds in this series with improved properties is ongoing. A part of this work is described here. Replacement of the two aromatic moieties of the PETT compounds by various substituted or unsubstituted heteroaromatic rings was investigated. In addition, the effects of multiple substitution in the phenyl ring were also studied. The antiviral activities were determined on wild-type and constructed mutants of HIV-1 RT and on wild-type HIV-1 and mutant viruses derived thereof, Ile100 and Cys181, in cell culture assays. Some selected compounds were determined on double-mutant viruses, HIV-1 (Ile 100/Asn103) and HIV-1 (Ile100/Cys181). A number of highly potent analogs were synthesized. These compounds displayed IC50's against wild-type RT between 0.6 and 5 nM. In cell culture, these agents inhibited wild-type HIV-1 with ED50's between 1 and 5 nM in MT-4 cells. In addition, these derivatives inhibited mutant HIV-1 RT (Ile 100) with IC50's between 20 and 50 nM and mutant HIV-1 RT (Cys 181) with IC50's between 4 and 10 nM, and in cell culture they inhibited mutant HIV-1 (Ile100) with ED50's between 9 and 100 nM and mutant HIV-1 (Cys181) with ED50's between 3 and 20 nM.     

N-[2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide: a potent and selective dopamine D4 ligand

A series of new 1-aryl-4-alkylpiperazines containing a terminal benzamide fragment or a tetralin-1-yl nucleus on the alkyl chain were synthesized and tested for binding at cloned human dopamine D4 and D2 receptor subtypes. A SAFIR (structure-affinity relationship) study on this series is herein discussed. The most relevant D4 receptor affinities were displayed by N-[omega-[4-arylpiperazin-1-yl]alkyl]-methoxybenzamides (compounds 5, 16-20), their IC50 values ranging between 0.057 and 7.8 nM. Among these, N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide (17) emerged since it exhibited very high affinity for dopamine D4 receptor (IC50 = 0.057 nM) with selectivity of >10 000 for the D4 versus the D2 receptor; compound 17 was also selective versus serotonin 5-HT1A and adrenergic alpha1 receptors.