David P. Rotella

Phosphodiesterase 5 inhibitors: current status and potential applications

Phosphodiesterase enzymes convert cyclic GMP and cyclic AMP to the corresponding nucleotide monophosphates. Phosphodiesterase 5 (PDE5) inhibition is now a widely accepted and efficacious therapeutic option for the treatment of erectile dysfunction in men, as a result of extensive clinical experience with sildenafil and other new PDE5 inhibitors. Research in the field continues at a substantial level to identify new, selective PDE5 inhibitors and to investigate their usefulness and activity in other areas. This review summarizes recent clinical trials with PDE5 inhibitors, advances in medicinal chemistry, and other activities and potential applications of this class of compounds.

Progress in the Discovery and Development of Heat Shock Protein 90 (Hsp90) Inhibitors

The discovery and clinical development of heat shock protein 90 (Hsp90) inhibitors continue to progress. A number of Hsp90 inhibitors are in clinical trials, and preclinical discoveries of new chemotypes that bind to distinct regions in the protein as well as isoform selective compounds are active areas of research. This review will highlight progress in the field since 2010.

Stereoselective synthesis of erythro α-amino epoxides

Abstract The stereoselective reduction of bromomethyl ketones derived from leucine, phenylalanine, alanine and valine is described using borohydride reagents. The Boc-amino alcohol product has erythro stereochemistry at the carbinol center as deduced by conversion to Boc-amino epoxides. These oxiranes are useful for the preparation of hydroxyethylene peptide isosteres.

Chloroperoxidase mediated halogenation of phenols

Halophenols are among the many varied types of halogenated organic compounds occurring in the ecosystem. Primarily because of pollution research, the chlorophenols found in most environmental samples are believed to be the result of man-related activities. However, several of the halophenols also have a natural origin. Since environmental investigation of halogenated pollutants usually leads to the ultimate source(s) of these substances, careful assessment must be made regarding the presence, causes and effects of halophenols found in the biosphere. The emerging picture strongly indicates that many organisms contain haloperoxidase enzymes which catalyze the formation of a carbon-halogen covalent bond leading to the formation of halogenated natural products. In this study, the authors employed a fungal enzyme, chloroperoxidase (CPO) obtained from Caldariomyces fumago. Chloroperoxidase has been well utilized as a model in the study of biological halogenation. Their intent was to use the enzyme as a means to predict potential halogenation of phenols in the ecosystem.

Chapter 1 Potential CNS Applications for Phosphodiesterase Enzyme Inhibitors

Publisher Summary Phosphodiesterases (PDEs) inhibition, which leads to an increase in cyclic nucleotide concentration, represents a means by which cellular signaling pathways can be influenced for therapeutic benefit. The detection of PDE enzymes in the central nervous system (CNS) has stimulated interest in exploring potential applications of PDE inhibitors for treating CNS disorders such as Alzheimers disease and other cognitive malfunctions, depression, anxiety, and schizophrenia. This chapter focuses on these therapeutic opportunities and new developments in the medicinal chemistry and biology associated with selected members of the PDE family, in particular PDEs 2, 4, 9, and 10. PDE2 is a mixed specificity PDE that is expressed in the CNS in the hippocampus, cortex, and striatum. This expression pattern stimulated the study of PDE2 inhibitors for treatment of cognitive disorders. One of the most recent and thoroughly explored compounds is Bay 60-7550. MEM1414 is a PDE4 inhibitor from Memory Pharmaceuticals that is in clinical development for potential use in Alzheimers disease. Thienopyrimidinones are claimed to be potent PDE9 inhibitors with excellent selectivity versus PDE5 (4800-fold). PDE10 inhibitors is reported to have a PDE10 IC50 (inhibitory concentration 50) value of approximately 1nM. Quinoline 14 is representative of a family of PDE10 inhibitors derived ultimately from papaverine.

WS-50030 [7-{4-[3-(1H-inden-3-yl)propyl]piperazin-1-yl}-1,3-benzoxazol-2(3H)-one]: A Novel Dopamine D2 Receptor Partial Agonist/Serotonin Reuptake Inhibitor with Preclinical Antipsychotic-Like and Antidepressant-Like Activity

The preclinical characterization of WS-50030 [7-{4-[3-(1H-inden-3-yl)propyl]piperazin-1-yl}-1,3-benzoxazol-2(3H)-one] is described. In vitro binding and functional studies revealed highest affinity to the D2 receptor (D2L Ki, 4.0 nM) and serotonin transporter (Ki, 7.1 nM), potent D2 partial agonist activity (EC50, 0.38 nM; Emax, 30%), and complete block of the serotonin transporter (IC50, 56.4 nM). Consistent with this in vitro profile, WS-50030 (10 mg/kg/day, 21 days) significantly increased extracellular 5-HT in the rat medial prefrontal cortex, short-term WS-50030 treatment blocked apomorphine-induced climbing (ID50, 0.51 mg/kg) in a dose range that produced minimal catalepsy in mice and induced low levels of contralateral rotation in rats with unilateral substantia nigra 6-hydroxydopamine lesions (10 mg/kg i.p.), a behavioral profile similar to that of the D2 partial agonist aripiprazole. In a rat model predictive of antipsychotic-like activity, WS-50030 and aripiprazole reduced conditioned avoidance responding by 42 and 55% at 10 mg/kg, respectively. Despite aripiprazoles reported lack of effect on serotonin transporters, long-term treatment with aripiprazole or WS-50030 reversed olfactory bulbectomy-induced hyperactivity at doses that did not reduce activity in sham-operated rats, indicating antidepressant-like activity for both compounds. Despite possessing serotonin reuptake inhibitory activity in addition to D2 receptor partial agonism, WS-50030 displays activity in preclinical models predictive of antipsychotic- and antidepressant efficacy similar to aripiprazole, suggesting potential efficacy of WS-50030 versus positive and negative symptoms of schizophrenia, comorbid mood symptoms, bipolar disorder, major depressive disorder, and treatment-resistant depression. Furthermore, WS-50030 provides a tool to further explore how combining these mechanisms might differentiate from other antipsychotics or antidepressants.

Tetrahydrocarbazole-based serotonin reuptake inhibitor/dopamine D2 partial agonists for the potential treatment of schizophrenia.

A 5-fluoro-tetrahydrocarbazole serotonin reuptake inhibitor (SRI) building block was combined with a variety of linkers and dopamine D2 receptor ligands in an attempt to identify potent D2 partial agonist/SRI molecules for treatment of schizophrenia. This approach has the potential to treat a broader range of symptoms compared to existing therapies. Selected compounds in this series demonstrate high affinity for both targets and D2 partial agonism in cell-based and in vivo assays.

Potent dihydroquinolinone dopamine D2 partial agonist/serotonin reuptake inhibitors for the treatment of schizophrenia.

A dihydroquinolinone moiety was found to be a potent serotonin reuptake inhibitor pharmacophore when combined with certain amines. This fragment was coupled with selected D(2) ligands to prepare a series of dual acting compounds with attractive in vitro profiles as dopamine D(2) partial agonists and serotonin reuptake inhibitors. Structure-activity studies revealed that the linker plays a key role in contributing to D(2) affinity, function, and SRI activity.

The effect of Pyrrolo[3,4-c]carbazole derivatives on spinal cord ChAT activity

Abstract Pyrrolo[3,4-c]carbazole derivatives were prepared as potential neurotrophic agents. The compounds were assayed for their ability to stimulate choline acetyltransferase (ChAT) activity in embryonic rat spinal cord cultures. These simplified K252a derivatives, although less potent and efficacious, have led to the identification of minimal structural requirements for K252a neurotrophic activity.

Expression, purification, and inhibition profile of dihydrofolate reductase from the filarial nematode Wuchereria bancrofti

Filariasis is a tropical disease caused by the parasitic nematodes Wuchereria bancrofti and Brugia malayi. Known inhibitors of dihydrofolate reductase (DHFR) have been previously shown to kill Brugia malayi nematodes and to inhibit Brugia malayi DHFR (BmDHFR) at nanomolar concentrations. These data suggest that BmDHFR is a potential target for the treatment of filariasis. Here, protocols for cloning, expression and purification of Wuchereria bancrofti DHFR (WbDHFR) were developed. The Uniprot entry J9F199-1 predicts a 172 amino acid protein for WbDHFR but alignment of this sequence to the previously described BmDHFR shows that this WbDHFR sequence lacks a crucial, conserved 13 amino acid loop. The presence of the loop in WbDHFR is supported by a noncanonical splicing event and the loop sequence was therefore included in the gene design. Subsequently, the KM for dihydrofolate (3.7 ± 2 μM), kcat (7.4 ± 0.6 s-1), and pH dependence of activity were determined. IC50 values of methotrexate, trimethoprim, pyrimethamine, raltitrexed, aminopterin, (-)-epicatechin gallate, (-)-epicatechin, and vitexin were measured for WbDHFR and BmDHFR. Methotrexate and structurally related aminopterin were found to be effective inhibitors of WbDHFR, with an KI of 1.2 ± 0.2 nM and 2.1 ± 0.5 nM, respectively, suggesting that repurposing of known antifolate compound may be an effective strategy to treating filariasis. Most compounds showed similar inhibition profiles toward both enzymes, suggesting that the two enzymes have important similarities in their active site environments and can be targeted with the same compound, once a successful inhibitor is identified.