Biaryl ethers as potent allosteric inhibitors of reverse transcriptase and its key mutant viruses: aryl substituted pyrazole as a surrogate for the pyrazolopyridine motif.

Biaryl ethers were recently reported as potent NNRTIs. Herein, we disclose a detailed effort to modify the previously reported compound 1. We have designed and synthesized a series of novel pyrazole derivatives as a surrogate for pyrazolopyridine motif that were potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells.

Substituted tetrahydroquinolines as potent allosteric inhibitors of reverse transcriptase and its key mutants.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key elements of multidrug regimens, called HAART (Highly Active Antiretroviral Therapy), that are used to treat HIV-1 infections. Elucidation of the structure-activity relationships of the thiocarbamate moiety of the previous published lead compound 2 provided a series of novel tetrahydroquinoline derivatives as potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells. The SAR optimization, mutation profiles, preparation of compounds, and pharmacokinetic profile of compounds are described.

Contrast-enhanced Spectral Mammography: Modality-Specific Artifacts and Other Factors Which May Interfere with Image Quality.

RATIONALE AND OBJECTIVES: Contrast-enhanced spectral mammography (CESM) uses full field digital mammography with the added benefit of intravenous contrast administration to significantly reduce false-positive and false-negative results and improve specificity while maintaining high sensitivity. For CESM to fulfill its purpose, one should be aware of possible artifacts and other factors which may interfere with image quality, and attention should be taken to minimize these factors. MATERIALS AND METHODS: This pictorial demonstration will depict types of artifacts detected and other factors that interfere with image acquisition in our practice since CESM implementation. RESULTS: Many of the artifacts and other factors we have encountered while using CESM have simple solutions to resolve them. CONCLUSION: The illustrated artifacts and other factors interfering with image quality will serve as a useful reference to anyone using CESM.

Contrast-enhanced Spectral Mammography: Technique, Indications, and Clinical Applications.

RATIONALE AND OBJECTIVES: Contrast-enhanced spectral mammography (CESM) combines the benefits of full field digital mammography with the concept of tumor angiogenesis. Technique and practical applications of CESM are discussed. MATERIALS AND METHODS: An overview of the technique is followed by a demonstration of practical applications of CESM in our practice. RESULTS: We have successfully implemented CESM into our practice as a screening, diagnostic, staging, and treatment response tool. CONCLUSION: It is important to understand the technique of CESM and how to incorporate it into practice.

Case report: ductal carcinoma in situ in the male breast.

High-grade ductal carcinoma in situ is incredibly rare in male patients. The prognosis for ductal carcinoma in situ (DCIS) in a male patient is the same as it would be for a female with the same stage disease; therefore, early recognition and diagnosis are of the utmost importance. We present a case of a male with unilateral invasive ductal carcinoma who was diagnosed with DCIS in the contralateral breast. The DCIS presented as microcalcifications on mammography and was found to be biopsy proven grade 3 papillary DCIS. This case also illustrates the importance of family history and risk factors, all of which need to be evaluated in any male presenting with a breast mass or nipple discharge.

Biaryl ethers as novel non-nucleoside reverse transcriptase inhibitors with improved potency against key mutant viruses.

Biaryl ethers were recently reported as potent NNRTIs. Herein we disclose a detailed SAR study that led to the biaryl ether 6. This compound possessed excellent potency against WT RT and key clinically observed RT mutants and had an excellent pharmacokinetic profile in rats, dogs, and rhesus macaques. The compound also exhibited a clean safety profile in preclinical safety studies.

2-Aminobenzophenones as a novel class of bradykinin B1 receptor antagonists.

Selective bradykinin (BK) B 1 receptor antagonists could be novel therapeutic agents for the treatment of pain and inflammation. Elucidation of the structure activity relationships of the structurally novel HTS lead compound 1 provided potent hBK B 1 receptor antagonists with excellent receptor occupancy in the CNS of hBK B 1 transgenic rats.

Discovery of platencin, a dual FabF and FabH inhibitor with in vivo antibiotic properties.

Emergence of bacterial resistance is a major issue for all classes of antibiotics; therefore, the identification of new classes is critically needed. Recently we reported the discovery of platensimycin by screening natural product extracts using a target-based whole-cell strategy with antisense silencing technology in concert with cell free biochemical validations. Continued screening efforts led to the discovery of platencin, a novel natural product that is chemically and biologically related but different from platensimycin. Platencin exhibits a broad-spectrum Gram-positive antibacterial activity through inhibition of fatty acid biosynthesis. It does not exhibit cross-resistance to key antibiotic resistant strains tested, including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate S. aureus, and vancomycin-resistant Enterococci. Platencin shows potent in vivo efficacy without any observed toxicity. It targets two essential proteins, beta-ketoacyl-[acyl carrier protein (ACP)] synthase II (FabF) and III (FabH) with IC50 values of 1.95 and 3.91 microg/ml, respectively, whereas platensimycin targets only FabF (IC50 = 0.13 microg/ml) in S. aureus, emphasizing the fact that more antibiotics with novel structures and new modes of action can be discovered by using this antisense differential sensitivity whole-cell screening paradigm.