Schuyler Adam Antane

Synthesis and potassium channel opening activity of substituted 10H-benzo[4,5]furo[3,2-b]indole-and 5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acids.

Compounds in a structurally novel series of substituted 10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acids and related 5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acids were prepared and shown to possess potent, bladder-selective smooth muscle relaxant properties and thus are potentially useful for the treatment of urge urinary incontinence. Electrophysiological studies using rat detrusor myocytes have demonstrated that prototype compound 7 produces a significant increase in hyperpolarizing current, which is iberiotoxin (IbTx)-reversed, thus consistent with activation of the large-conductance Ca(2+)-activated potassium channel (BK(Ca)).

Naphthyl tetronic acids as multi-target inhibitors of bacterial peptidoglycan biosynthesis.

Since the discovery of penicillin in 1929, many important antibiotic agents have made significant contributions to the prevention and treatment of infections caused by bacteria. Despite these remarkable achievements, infections are still the second-leading cause of death worldwide and remain a major public health problem. Clearly, there is great need for novel antibacterial agents to address resistance problems associated with current antibiotics. Toward this end, three broad strategies have been recently employed in the search for new leads: high-throughput screening of large compound libraries, genomics, and combinatorial biosynthesis. Although some limitations of the former approach to targets in bacterial peptidoglycan biosynthesis have been reported, the peptidoglycan biosynthetic pathway remains an attractive target, validated in the clinic with fosfomycin and vancomycin. Peptidoglycan biosynthesis is a complex process, which involves three main stages: a) cytoplasmic soluble enzymes that include MurA–F, b) membrane-bound enzymes that include MraY and MurG, and finally c) transglycosylases and transpeptidases, which act external to the cytoplasmic membrane. The Mur enzymes are unique to bacteria and are involved in essential functions of both Gram-positive and Gram-negative organisms. Another attractive aspect of Mur enzyme inhibitors is the potential to be bactericidal, leading to cell lysis and bacterial death. Inhibitors of peptidoglycan biosynthesis initiate a complex process of gene expression resulting in the induction of MurA and Mur I in Gram-positive bacteria to compensate for the slower rate of peptidoglycan biosynthesis. Several classes of natural products or their semisynthetic derivatives represented by liposidomycins, amphomycins, and muraymycins are inhibitors of MraY, whereas nisin, ramoplanin, and mersacidin are lipid II inhibitors. In the last decade a few small-molecule inhibitors of the Mur enzymes have been reported, including sesquiterpene lactones, 5-sulfonoxyanthranilic acids T6361 and T6362, UDP-MurNAc (MurA), imidazolinones, 4-thiazolidinones, thienopyrazoles, phosphinates (MurB), peptidosulfonamides, 3-cyanothiophenes (MurF), and d-glutamic acid analogues (Mur I). Despite the discovery of small-molecule inhibitors of various Mur enzymes, many limitations have been noted, including poor antibacterial activities in cells. In parallel, a number of new assay formats for the identification of Mur enzyme inhibitors have been described based on different platforms such as ultra-efficient affinity HTS, LC– MS, TLC, HPLC, and solid-support TLC. Our efforts in identifying Mur enzyme inhibitors were based on an initial pathway screen searching for inhibitors of multiple enzymes, MurA–F. Hits in this assay were evaluated against the individual Mur enzymes for lead optimization. Using this strategy, we identified two classes of inhibitors : 3,5-dioxopyrazolidines and pulvinones, with activities against several of the Mur enzymes. Inhibitors of multiple Mur enzymes are attractive given the essential role of each Mur enzyme in peptidoglycan biosynthesis. This strategy may prevent the development of drug resistance through the multi-target hypothesis. Herein we report on the SAR of the naphthyl tetronic acids and highlight their binding to the E. coli enzyme MurB. The target naphthylfuran-2-ones 5a–k were prepared by a three-step process starting from 3-bromo-4-methoxy-5H-furan2-one (1) and the appropriately substituted aldehydes 2 (Scheme 1). Bromofuranone 1 was acquired by bromination of the commercially available 4-methoxy-5H-furan-2-one with Nbromosuccinimide in carbon tetrachloride at reflux. Deprotonation of 2 at C5 with lithium isopropylcyclohexylamide (LICA) followed by an aldol reaction with substituted aldehydes 2 mediated by anhydrous ZnCl2 afforded diastereomeric alcohols, which were converted into their mesylate or chloride derivatives in situ followed by elimination to generate the exocyclic double bond of 3 in the thermodynamically more stable Z configuration. The key step involved a Suzuki cross-coupling of 3 with aryl boronic acids catalyzed by either [PdACHTUNGTRENNUNG(PPh3)4] or [PdCl2ACHTUNGTRENNUNG(dppf)2] to afford the methoxyfuranones 4a–k. Demethylation of methoxyfuranones 4a–k with lithium bromide in the final step afforded the desired naphthylfuran-2ones 5a–k. Purification by silica gel column chromatography was followed by an acid wash of the collected fractions to restore the acidic functionality. A panel of nine enzymes was used to assess the abilities of the naphthylfuranones to inhibit the Mur enzymes, and thus to define SAR trends for multiple enzyme inhibition (Table 1). The four isomeric bis-naphthyl compounds (Entries 1–4) were evaluated to determine whether there is a preference for aor blinked naphthyl groups at either C3 or C5. The trend seems to favor C3 b and C5 a substitution. Replacement of naphthyl with p-chlorophenyl (Entries 5–8) gave compounds 5e–h with good broad-spectrum activity against the Mur enzymes, thus confirming the desired SAR trend. Further optimization of the C5 a methylidene naphthyl derivative 5h by changing the p[a] Dr. T. S. Mansour, Dr. B. Rasmussen, Dr. G. Krishnamurthy, C. Smeltzer, Dr. Y. Yang, Dr. A. Severin, P. J. Petersen, Dr. G. Singh Medicinal Chemistry, Wyeth Research 401 North Middletown Road, Pearl River, NY 10965 (USA) Fax: (+1)845-602-5580 E-mail : mansout@wyeth.com [b] Dr. C. E. Caufield, K. M. Morris, S. Naughton, S. Antane, Dr. D. Quagliato Wyeth Research, CN 8000, Princeton, NJ 08543 (USA) [c] Dr. R. Chopra, K. Svenson, Dr. J. Bard Wyeth Research, Cambridge, MA 02140 (USA)

Chloromethyl sulfones from sulfonyl chlorides via a one-pot procedure

Abstract A simplified one‐pot transformation of a diverse set of aryl‐ and heteroaryl‐sulfonyl chlorides into the corresponding chloromethyl sulfones is described.

3-(Arylsulfonyl)-1-(azacyclyl)-1H-indoles are 5-HT6 receptor modulators

Novel 3-(arylsulfonyl)-1-(azacyclyl)-1H-indoles 6 were synthesized as potential 5-HT(6) receptor ligands, based on constraining a basic side chain as either a piperidine or a pyrrolidine. Many of these compounds had good 5-HT(6) binding affinity with K(i) values <10nM. Depending on substitution, both agonists (e.g., 6o: EC(50)=60nM, E(max)=70%) and antagonists (6y: IC(50)=17 nM, I(max)=86%) were identified in a 5-HT(6) adenylyl cyclase assay.

Novel 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines are potent 5-HT6 agonists

A series of 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 10a-z was prepared as novel 5-HT(6) ligands. The best compounds were high affinity, full agonists at 5-HT(6) receptors. Several agonists demonstrated good selectivity over other serotonergic and dopaminergic receptors. Acute administration of selective agonist 10e significantly increased extracellular GABA concentrations in rat frontal cortex. This compound also reduced adjunctive drinking behavior in the rat schedule-induced polydipsia assay, possibly predictive of efficacy in obsessive compulsive disorder and other anxiety related disorders.

1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-pyrrolopyridines are 5-HT6 receptor ligands

1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-pyrrolopyridines were prepared. Binding assays indicated they are 5-HT(6) receptor ligands, among which 6f and 6g showed high affinity for 5-HT(6) receptors with K(i)=3.9 and 1.7 nM, respectively.

Preparation of a Series of Aryl Isonipecotic Acids Using Microwave Irradiation

Abstract Rapid parallel synthesis of arylisonipecotic acids was achieved using microwave irradiation of a palladium catalyzed amination reaction.