John E. Starrett

Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)adenine

9-(2-Phosphonylmethoxyethyl)adenine (PMEA; 1) was acylated with chloromethyl pivalate to afford bis(pivaloyloxymethyl) PMEA (2). The ester prodrug demonstrated enhanced in vitro potency against HSV-2 greater than 150-fold higher than the parent compound. The antiviral activity of 2 was 50-fold better than PMEA against HSV-1, and equipotent against HIV and HCMV. The toxicity of 2 was studied in both resting and growing cells.

The Pharmacology and Molecular Biology of Large-Conductance Calcium = Activated (BK) Potassium Channels

Publisher Summary This chapter summarizes the current status of pharmacological development targeted at an important class of K+ channel, the BK channel. BK Channels are a phenotypically diverse group of voltage-dependent ion channels with a range of single-channel conductance values, sensitivities to [Ca2+]in, and a widespread localization throughout excitable and nonexcitable tissues. Ca2+-activated K+ channels, including BK channels, are widely distributed K+ channels with one property in common, their dependence on intracellular Ca2+ for activation. It is this property that separates them from other K+ channels and makes them so potentially important from a functional point of view. For discussion of the pharmacology of BK channels, the chapter takes the approach that the initial importance of the development of pharmacology for an ion channel (or any receptor) is the utility of these various agents, both inhibitors and activators, to be used as tools to investigate various aspects of the channels function. In addition, pharmacological agents can be used to determine the distribution of the channel. In some cases, they can be used to isolate and eventually clone channel proteins. Although this order has been reversed in some previous cases, this is increasingly the process by which ion channel drug discovery is likely to proceed. In the specific case of the development of the pharmacology of BK channels, serendipity certainly played a role in the discovery of some of the original compounds that interact with these channels, but several groups have subsequently directed their efforts to the development of compounds specifically targeted for these channels. The rapid advances in the understanding of the molecular pharmacology of these channels, their functions, and their localization at the cellular and regional level all are anticipated to contribute to advances in the pharmaceutical utility of BK channel-directed drugs.

Preparation of the geometric isomers of DDC, DDA, D4C and D4T as potential anti-HIV agents

Abstract β-L-ddC ( 5 ), β-L-ddA ( 7 ), β-L-d4T ( 7 ) and β-L-d4C ( 8 ) (enantiomers of natural dideoxynucleoside analogues with known potent HIV activity) were prepared as potential anti-HIV agents.

Role of Retinoic Acid Receptor Gamma in the Rhino Mouse and Rabbit Irritation Models of Retinoid Activity

The three retinoic acid receptors (RAR alpha, RAR beta and RAR gamma) are known to modulate the transcription of target genes through interaction of the individual receptors with their naturally occurring ligand, retinoic acid (RA). Since RA has multiple effects in vivo, considerable effort has recently been devoted to finding selective compounds to elucidate the functions of individual receptors and to relate these functions to specific in vivo effects. The racemic synthetic retinoid 6-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)hydroxy-methyl]-2- naphthalene carboxylic acid has recently been identified as an RAR gamma-selective agonist. A synthetic method involving lipase-mediated transformation has been developed to prepare the individual enantiomers. Discrimination between the two enantiomers is seen in both transcriptional activity and binding to recombinant receptors with the (S)-enantiomer being the more active. Differences between the two compounds are also seen in the Rhino mouse utriculi reduction assay and the rabbit irritation model. In both animal models, the (S)-enantiomer consistently gave a greater response. Taken together, these results suggest that the activity and irritation seen with RA and related compounds is receptor mediated. Further, the strong selectivity of the compounds reported here for RAR gamma suggests that this receptor plays an important role in these in vivo biological activities. The discrimination between these enantiomers may be useful in the design of novel retinoids with uniquely defined biological properties.

Structural modifications of 6-naphthalene-2-carboxylate retinoids

Abstract The keto linker of 2-naphthoate retinoid 1 has been found nonessential for RAR transactivation activity and can be replaced with heteroatoms such as S, O, N without significant reduction of the activity. On the other hand, substitutions on the aromatic rings of retinoids 1 and 2 resulted in analogs with reduced potentcy and RAR selectivity.

Discovery of (S,E)-3-(2-fluorophenyl)-N-(1-(3-(pyridin-3-yloxy)phenyl)ethyl)-acrylamide as a potent and efficacious KCNQ2 (Kv7.2) opener for the treatment of neuropathic pain

Acrylamide (S)-6, a potent and efficacious KCNQ2 (Kv7.2) opener, demonstrated significant activity in two models of neuropathic pain and in the formalin test, suggesting that KCNQ2 openers may be useful in the treatment of neuropathic pain including diabetic neuropathy.

APPLICATION OF THE HECK REACTION IN THE SYNTHESIS OF TRUNCATED NAPHTHOIC ACID RETINOIDS

Abstract A series of truncated naphthoic acid retinoids have been prepared using the Heck reaction. These retinoids were evaluated in the RAR transactivation assay in vitro and in the utriculi reduction assay in vivo. It has been found that the naphthalene ring of the retinoids is crucial for their retinoid activity and receptor selectivity.

Synthesis, Anti-Hiv Activity, and Biological Properties of 2′,3′-Didehydro-2′,3′-Dideoxythwidine (d4T)

Abstract D4T is a thymidine analogue with an in vitro potency against HIV comparable to that of AZT but is less toxic to a variety of cell lines including human hemopoietic progenitor cells.