Synthesis and evaluation of azabicyclo[3.2.1]octane derivatives as potent mixed vasopressin antagonists.

A series of biaryl amides containing an azabicyclooctane amine headpiece were synthesized and evaluated as mixed arginine vasopressin (AVP) receptor antagonists. Several analogues, including 8g, 12g, 13d, and 13g, were shown to have excellent V(1a)- and good V(2)-receptor binding affinities. Compound 13d was further profiled for drug-like properties and for an in vitro comparison with conivaptan, the program's mixed V(1a)/V(2)-receptor antagonist standard.

Synthesis, potency, and in vivo evaluation of 2-piperazin-1-ylquinoline analogues as dual serotonin reuptake inhibitors and serotonin 5-HT1A receptor antagonists.

On the basis of the previously reported clinical candidate, SSA-426 (1), a series of related 2-piperazin-1-ylquinoline derivatives 3-16 were synthesized and evaluated as dual-acting serotonin (5-HT) reuptake inhibitors and 5-HT1A receptor antagonists. In particular, compound 7 exhibits potent functional activities at both the 5-HT transporter and 5-HT1A receptor, good selectivity over the alpha1-adrenergic and dopaminergic receptors, acceptable pharmacokinetic properties, and a favorable in vivo profile.

Normal-phase automated mass-directed HPLC purification of a pyrrolobenzodiazepine library with vasopressin agonist activity.

A 23-member library of pyrrolobenzodiazepine derivatives with vasopressin agonist activity was purified on a 100-mg per injection scale using normal-phase (NP) automated mass-directed HPLC. Analytical NP APCI-LC/MS on an experimental monolith silica CN column utilizing gradients of methanol in ethoxynonafluorobutane (hexane-like solvent) was used to provide data on chromatographic purity and ionization of the solutes. The analytical data collected were used to program a preparative LC/MS instrument for "smart" fraction collection based on the protonated molecular ion of the component of interest. Preparative HPLC was carried out on a preparative cyano column with gradients of polar organic solvents in heptane containing n-propylamine as a basic additive. Flow rates twice as high as conventional ones were used for purification of library compounds. Small aliquots of the preparative flow were mixed with makeup solvent and introduced into an APCI source of a quadrupole mass spectrometer, which triggered collection of solutes. Two methods with fixed instrument parameters were used for purification. The system utilized commercially available instrumentation and software, which provided excellent recovery and purity of the library components and appeared to be useful as a fast and efficient alternative to traditional purification technologies based on reversed-phase LC/MS.

Advances toward new antidepressants with dual serotonin transporter and 5-HT1A receptor affinity within a class of 3-aminochroman derivatives. Part 2.

Novel compounds combining a 5-HT 1A moiety (3-aminochroman scaffold) and a 5-HT transporter (indole analogues) linked through a common basic nitrogen via an alkyl chain attached at the 1- or 3-position of the indole were evaluated for dual affinity at both the 5-HT reuptake site and the 5-HT 1A receptor. Compounds of most interest were found to have a 5-carbamoyl-8-fluoro-3-amino-3,4-dihydro-2 H-1-benzopyran linked to a 3-alkylindole (straight chain), more specifically substituted with a 5-fluoro (( R)-(-)- 35c), 5-cyano ((-)- 52a), or 5,7-difluoro ((-)- 52g). Several factors contributed to 5-HT 1A affinity, serotonin rat transporter affinity, and functional antagonism in vitro. Although most of our analogues showed good to excellent affinities at both targets, specific features such as cyclobutyl substitution on the basic nitrogen and stereochemistry at the 3-position of the chroman moiety seemed necessary for antagonism at the 5-HT 1A receptor. Branched linkers seemed to impart antagonism even as racemates; however, the potency of these analogues in the functional assay was not desirable enough to further pursue these compounds.

Pyrazolidine-3,5-diones and 5-hydroxy-1H-pyrazol-3(2H)-ones, inhibitors of UDP-N-acetylenolpyruvyl glucosamine reductase.

A series of pyrazolidine-3,5-dione and 5-hydroxy-1H-pyrazol-3(2H)-one inhibitors of Escherichia coli UDP-N-acetylenolpyruvyl glucosamine reductase (MurB) has been prepared. The 5-hydroxy-1H-pyrazol-3(2H)-ones show low micromolar IC(50) values versus E. coli MurB and submicromolar minimal inhibitory concentrations (MIC) against Staphylococcus aureus GC 1131, Enterococcus faecalis GC 2242, Streptococcus pneumoniae GC 1894, and E. coli GC 4560 imp, a strain with increased outer membrane permeability. None of these compounds show antimicrobial activity against Candida albicans, a marker of eukaryotic toxicity. Moreover, these compounds inhibit peptidoglycan biosynthesis, as assessed by measuring the amount of soluble peptidoglycan produced by Streptococcus epidermidis upon incubation with compounds. A partial least squares projection to latent structures analysis shows that improving MurB potency and MIC values correlate with increasing lipophilicity of the C-4 substituent of the 5-hydroxy-1H-pyrazol-3(2H)-one core. Docking studies using FLO and PharmDock produced several binding orientations for these molecules in the MurB active site.

3,5-dioxopyrazolidines, novel inhibitors of UDP-N- acetylenolpyruvylglucosamine reductase (MurB) with activity against gram-positive bacteria.

A series of 3,5-dioxopyrazolidines was identified as novel inhibitors of UDP-N-acetylenolpyruvylglucosamine reductase (MurB). Compounds 1 to 3, which are 1,2-bis(4-chlorophenyl)-3,5-dioxopyrazolidine-4-carboxamides, inhibited Escherichia coli MurB, Staphyloccocus aureus MurB, and E. coli MurA with 50% inhibitory concentrations (IC50s) in the range of 4.1 to 6.8 microM, 4.3 to 10.3 microM, and 6.8 to 29.4 microM, respectively. Compound 4, a C-4-unsubstituted 1,2-bis(3,4-dichlorophenyl)-3,5-dioxopyrazolidine, showed moderate inhibitory activity against E. coli MurB, S. aureus MurB, and E. coli MurC (IC50s, 24.5 to 35 microM). A fluorescence-binding assay indicated tight binding of compound 3 with E. coli MurB, giving a dissociation constant of 260 nM. Structural characterization of E. coli MurB was undertaken, and the crystal structure of a complex with compound 4 was obtained at 2.4 A resolution. The crystal structure indicated the binding of a compound at the active site of MurB and specific interactions with active-site residues and the bound flavin adenine dinucleotide cofactor. Peptidoglycan biosynthesis studies using a strain of Staphylococcus epidermidis revealed reduced peptidoglycan biosynthesis upon incubation with 3,5-dioxopyrazolidines, with IC50s of 0.39 to 11.1 microM. Antibacterial activity was observed for compounds 1 to 3 (MICs, 0.25 to 16 microg/ml) and 4 (MICs, 4 to 8 microg/ml) against gram-positive bacteria including methicillin-resistant S. aureus, vancomycin-resistant Enterococcus faecalis, and penicillin-resistant Streptococcus pneumoniae.

Pyridobenzodiazepines: a novel class of orally active, vasopressin V2 receptor selective agonists.

Our efforts in seeking low molecular weight agonists of the antidiuretic peptide hormone arginine vasopressin (AVP) have led to the identification of the clinical candidate WAY-151932 (VNA-932). Further exploration of the structural requirements for agonist activity has provided another class of potent, orally active, non-peptidic vasopressin V2 receptor selective agonists exemplified by the 5,11-dihydro-pyrido[2,3-b][1,5]benzodiazepine as a candidate for further development.

Use of structure-based drug design approaches to obtain novel anthranilic acid acyl carrier protein synthase inhibitors.

Acyl carrier protein synthase (AcpS) catalyzes the transfer of the 4'-phosphopantetheinyl group from the coenzyme A to a serine residue in acyl carrier protein (ACP), thereby activating ACP, an important step in cell wall biosynthesis. The structure-based design of novel anthranilic acid inhibitors of AcpS, a potential antibacterial target, is presented. An initial high-throughput screening lead and numerous analogues were modeled into the available AcpS X-ray structure, opportunities for synthetic modification were identified, and an iterative process of synthetic modification, X-ray complex structure determination with AcpS, biological testing, and further modeling ultimately led to potent inhibitors of the enzyme. Four X-ray complex structures of representative anthranilic acid ligands bound to AcpS are described in detail.

(4-Substituted-phenyl)-(5H-10,11-dihydro-pyrrolo [2,1-c][1,4] benzodiazepin-10-yl)-methanone derivatives as vasopressin receptor modulators.

Synthesis and structure-activity relationships (SAR) of arginine vasopressin (AVP) receptor modulators are described. Potent and selective compounds are prepared when the amide linkage connecting rings A and B of VPA-985 is replaced with a bond, CO, -O-, -S-, or -SO2- bond.

4-Alkyl and 4,4'-dialkyl 1,2-bis(4-chlorophenyl)pyrazolidine-3,5-dione derivatives as new inhibitors of bacterial cell wall biosynthesis.

Over 195 4-alkyl and 4,4-dialkyl 1,2-bis(4-chlorophenyl)pyrazolidine-3,5-dione derivatives were synthesized, utilizing microwave accelerated synthesis, for evaluation as new inhibitors of bacterial cell wall biosynthesis. Many of them demonstrated good activity against MurB in vitro and low MIC values against gram-positive bacteria, particularly penicillin-resistant Streptococcus pneumoniae (PRSP). Derivative 7l demonstrated antibacterial activity against both gram-positive and gram-negative bacteria. Derivatives 7f and 10a also demonstrated potent nanomolar Kd values in their binding to MurB.