Use of conformationally restricted benzamidines as arginine surrogates in the design of platelet GPIIb-IIIa receptor antagonists.

The use of 5,6-bicyclic amidines as arginine surrogates in the design of a novel class of potent platelet glycoprotein IIb-IIIa receptor (GPIIb-IIIa) antagonists is described. The additional conformational restriction offered by the bicyclic nucleus results in 20-400-fold increases in potency compared to the freely flexible, acyclic benzamidine counterpart. The design, synthesis, structure-activity relationships (SAR), and in vitro activity of this novel class of GPIIb-IIIa antagonists are presented.

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.

DL-tetrazol-5-ylglycine, a highly potent NMDA agonist: its synthesis and NMDA receptor efficacy.

At physiological pH, the spatial arrangement of the three charges of DL-tetrazol-5-ylglycine (5) could be viewed as similar to those found in certain conformations of the two excitatory amino acids (EAAs)--aspartic and glutamic acids. Given significant binding to one or more EAA receptors, 5 would offer unique modeling and perhaps biological opportunities. We have previously shown it to be the most potent NMDA agonist known, with a unique and marked in vitro neutrotoxicity at depolarizing concentrations. Now we report the details required for its synthesis, together with its potency and efficacy in two assays of functional activation of the NMDA receptor, namely agonist-influenced [3H]MK801 binding and agonist-induced release of the neurotransmitter [3H]-norepinephrine from brain slices. In both these assays DL-tetrazol-5-ylglycine proved to be more potent and efficacious than NMDA and cis-methanoglutamate. It was more potent than, and equally efficacious to, L-glutamate in [3H]MK801 binding. The structural features of 5 may well reflect optimal agonist interaction at the NMDA receptor site. (We considered the possibility that some decarboxylation of DL-tetrazol-5-ylglycine may have occurred during testing. This would give 5-(aminomethyl)tetrazole (13), the tetrazole acid analog of glycine; and glycine is involved in NMDA receptor activation. Compound 13 does not affect [3H]glycine binding at the strychnine-insensitive glycine binding site, and [3H]MK801 binding studies showed that the (aminomethyl)-tetrazole, even if is formed, would probably have no effect on the activity of tetrazol-5-ylglycine at the NMDA receptor.

Synthesis and biological evaluation of a series of parenteral 3'-quaternary ammonium cephalosporins.

The preparation and biological evaluation of a series of 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-methoximinoacetamido]cep halosporins, substituted at the 3'-position with monocyclic or bicyclic nitrogen-containing heterocycles are described. The resulting family of parenteral compounds displays a broad spectrum of antibacterial activity. Some compounds exhibit a similar level of Gram-negative activity to that of the "third-generation" cephalosporins with increased staphylococcal activity. The in vitro and in vivo antimicrobial activity, structure-activity relationships, beta-lactamase stability, and in vitro and in vivo pharmacological evaluations are presented.

Cephalosporanic acids: a new look at reactions at the C-3' position.

Nucleophilic displacement of the acetoxy group of cephalosporanic acids by thiols in aqueous solution at neutral pH provides 3-thiomethyl-substituted compounds with a broad spectrum of antibiotic activity. The aqueous displacement reaction is often destructive of much of the cephalosporanic acid, and products generally require extensive purification. Displacements at a lower pH are complicated by unwanted lactone formation. However, reactions conducted under acid conditions in a variety of anhydrous organic solvents give 3-thiomethyl-substituted compounds in very high yield and quality; no lactone formation is observed. The kinetics of the reaction support an SN1 mechanism. Protonation of the departing acetoxy group appears therefore critical; the more basic solvents, e.g. dimethylsulphoxide and N,N-dimethylformamide, significantly retard the rate of reaction.

Chemistry of cephalosporin antibiotics. 28. Preparation and biological activity of 3-(substituted)vinyl cephalosporins.

3-(Substituted)vinylcephem nuclei have been prepared by the reaction of 3-formylcephem derivatives with stabilized phosphoranes. Appropriate synthetic steps allowed preparation of a series of 3-ethoxycarbonylvinyl- and 3-carboxyvinylcephem derivatives bearing a variety of 7-acylamino functions. The phenoxyacetyl and thiopheneacetyl derivatives of the 3-cyanovinylcephem nucleus were also prepared. Although general gram-positive activity was comparable to cephalothin in many cases, against penicillin G resistant Staphylococcus aureus, the new cephalosporins were of low effectiveness. The 3-(substituted)vinyl cephalosporins had good activity against a number of gram-negative organisms. In some cases, this activity was excellent. The N-acetyl analogs had surprisingly good activity relative to N-acetyl-7-ACA. The phenylmalonoyl side-chain derivatives were shown to have an unusual antibacterial spectrum expansion (relative to previously known cephalosporins) to include activity against Serratia marcescens and Pseudomonas aeruginosa.