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The pyrophosphate mimic and broad spectrum antiviral phosphonoformic acid (PFA, foscarnet) was shown to freeze the pre-translocational state of the reverse transcriptase (RT) complex of the human immunodeficiency virus type 1 (HIV-1). However, PFA lacks a specificity domain, which is seen as a major reason for toxic side effects associated with the clinical use of this drug. Here, we studied the mechanism of inhibition of HIV-1 RT by the 4-chlorophenylhydrazone of mesoxalic acid (CPHM) and demonstrate that this compound also blocks RT translocation. Hot spots for inhibition with PFA or CPHM occur at template positions with a bias toward pre-translocation. Mutations at active site residue Asp-185 compromise binding of both compounds. Moreover, divalent metal ions are required for the formation of ternary complexes with either of the two compounds. However, CPHM contains both an anchor domain that likely interacts with the catalytic metal ions and a specificity domain. Thus, although the inhibitor binding sites may partly overlap, they are not identical. The K65R mutation in HIV-1 RT, which reduces affinity to PFA, increases affinity to CPHM. Details with respect to the binding sites of the two inhibitors are provided on the basis of mutagenesis studies, structure-activity relationship analyses with newly designed CPHM derivatives, and in silico docking experiments. Together, these findings validate the pre-translocated complex of HIV-1 RT as a specific target for the development of novel classes of RT inhibitors.

We have investigated a series of phenolic diaryl amino piperidine delta opioid receptor agonists, establishing the importance of the phenol functional group and substitution on the piperdine nitrogen for delta agonist activity and selectivity versus the mu and kappa opioid receptors. This study uncovered compounds with improved agonist potency and selectivity compared to the standard, non-peptidic delta agonist SNC-80. In vivo anti-nociceptive activity of analog 8e in two rodent models is discussed, demonstrating the potential of delta agonists to provide a novel mechanism for pain relief.

Several imidazole-based cyclohexyl amides were identified as potent CB-1 antagonists, but they exhibited poor oral exposure in rodents. Incorporation of a hydroxyl moiety on the cyclohexyl ring provided a dramatic improvement in oral exposure, together with a ca. 10-fold decrease in potency. Further optimization provided the imidazole 2-hydroxy-cyclohexyl amide 45, which exhibited hCB-1 Ki = 3.7 nM, and caused significant appetite suppression and robust, dose-dependent reduction of body weight gain in industry-standard rat models.

A series of pyrrolopyridinones was designed and synthesized as constrained analogs of the pyrazole CB-1 antagonist rimonabant. Certain examples exhibited very potent hCB-1 receptor binding affinity and functional antagonism with K i and K b values below 10 nM, and with high selectivity for CB-1 over CB-2 (>100-fold). A representative analog was established to cause significant appetite suppression and reduction in body weight gain in industry-standard rat models used to develop new therapeutics for obesity.

Histone deacetylase inhibitors (HDACs) have emerged as a novel class of antiproliferative agents. Utilizing structure-based design, the synthesis of a series of sulfonamide hydroxamic acids is described. Further optimization of this series by substitution of the terminal aromatic ring yielded HDAC inhibitors with good in vitro and in vivo activities.

Highly convergent, malonate alkylation based syntheses of the model macrocycles and their title investigations are reported. In the allylic ether dienophile case, a preference for tricycles with equatorial ether position was found at the transition state level. Ab initio calculations also show that the origin of this preference is not only steric but stereoelectronic as well. The enone dienophile case indicates that when the enone system is not totally twisted out of planarity by the macrocyclic environment, the Diels–Alder reaction follows the usual trend in terms of dienophile activation.

Stereocontrolled asymmetric synthesis and transannular Diels-Alder (TADA) reaction of a 14-membered trans-cis-cis (TCC) macrocyclic trienone with an activated dienophile leading to an A.B.C [6.6.6] tricycle having one angular methyl group is reported. The results of thermal and Lewis acid catalyzed TADA reaction are discussed.

Two different methods were used for the construction of optically active diarylmethylamines. Diastereoselective alkylation on an aldimine/oxazolidine 2a / 2b derived from ( R )/( S )-phenylglycinol or enantioselective reduction of 4-[η 6 -chromium tricarbonylbenzoyl] bromobenzene using chiral oxazoborolidine followed by amine introduction to furnish optically active diarylmethylamines.

Two different methods were used for the construction of optically active diarylmethylamines. Diastereoselective alkylation on an aldimine/oxazolidine 2a / 2b derived from ( R )/( S )-phenylglycinol or enantioselective reduction of 4-[η 6 -chromium tricarbonylbenzoyl] bromobenzene using chiral oxazoborolidine followed by amine introduction to furnish optically active diarylmethylamines.

Highly convergent, malonate alkylation based syntheses of the model macrocycles and their title investigations are reported. In the allylic ether dienophile case, a preference for tricycles with equatorial ether position was found at the transition state level. Ab initio calculations also show that the origin of this preference is not only steric but stereoelectronic as well. The enone dienophile case indicates that when the enone system is not totally twisted out of planarity by the macrocyclic environment, the Diels–Alder reaction follows the usual trend in terms of dienophile activation.