Design and synthesis of potent carboxylic acid DGAT1 inhibitors with high cell permeability.

A series of potent carboxylic acid DGAT1 inhibitors with high permeability were developed from a virtual screening hit. Strategies were employed to reduce Pgp substrate recognition and increase passive permeability, resulting in the discovery of a series showing good inhibition of cellular triglyceride synthesis. The mutagenic potential of prospective metabolites was evaluated in the Ames assay, and one aniline was shown to be devoid of mutagenicity.

[Imaging anatomy of the cranial nerves using 3.0 Tesla MRI: a practical review for clinicians]. / Anatomía de los nervios craneales con resonancia magnética de 3.0 Tesla: una revisión práctica para clínicos.

Magnetic resonance (MR) imaging is the method of choice to evaluate the cranial nerves (CN). These nerves constitute a group of structures that have acquired during their phylogenetic development a high degree of specialization. There are 12 pairs of CN to which we use their specific name or number. The olfactory (I) and optic (II) pairs are not real nerves but tracts from the encephalon. The spinal nerve (XI) derives from superior cervical segment of the spine. The other 9 pairs of CN are related with the brain stem. Although the skull base foramina can be seen on computed tomography, the nerves themselves can only be visualized in detail on MR. That means, in order to see the different segments of nerves I to XII, the right sequences must be used. It is important to provide detailed clinical information to the radiologist so that a tailored MR study can be performed. In this review, the basic imaging anatomy of the 12 CN is discussed and illustrated briefly with an emphasis on more advanced extra-axial anatomy, illustrated with high-resolution MR images. Clinicians looking for complete anatomic descriptions and/or MR illustrations are advised to consult specialized textbooks considering it is not possible to describe all of the anatomy in one article. This manuscript is intended to be a practical review for clinicians.

Acute Disseminated Encephalomyelitis: An Unusual Presentation of Human Immunodeficiency Virus Infection.

BACKGROUND: Acute disseminated encephalomyelitis (ADEM) is a rare inflammatory and demyelinating disorder of the central nervous system, with a distinct tendency to a perivenous localization of pathological changes. Children are the most affected population and frequently presented after exanthematous viral infections or vaccination. Due to the rarity of this disease, the annual incidence rate in the population is not precisely known. Case Presentation. Here, we present a 28-year-old male HIV-1 positive patient with an acute confusional state, a diminished alert status characterized by somnolence, hypoprosexia, and complex visual hallucinations. Neuroimages reported white matter demyelinating lesions, mainly affecting the semioval centers, the frontal lobe, and the left parietal lobe; hypointense on T1-weighted images, hyperintense on T2-weighted images and fluid-attenuated inversion recovery weighted images, DWI with restricted diffusion, and a parietal ring-enhancing lesion after IV gadolinium administration. Discussion. In HIV positive patients, the demyelinating disorders have a broader clinical spectrum that could be explained by the immunosuppressed state of the patients, the evolution of the disease, the use of medications, the opportunistic infections, and the environment. Due to this highly variable clinical spectrum, ADEM is a significant challenge for the physicians in HIV positive patients, causing a delay in the diagnosis and treatment. CONCLUSION: We suggest that ADEM should be considered among the differential diagnosis in HIV-infected patients with focal or multifocal neurological symptoms, particularly in encephalopathies with multifocal central nervous system involvement without severe immunosuppression.

Novel indazole non-nucleoside reverse transcriptase inhibitors using molecular hybridization based on crystallographic overlays.

A major problem associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of HIV is their lack of resilience to mutations in the reverse transcriptase (RT) enzyme. Using structural overlays of the known inhibitors efavirenz and capravirine complexed in RT as a starting point, and structure-based drug design techniques, we have created a novel series of indazole NNRTIs that possess excellent metabolic stability and mutant resilience.

Synthetic chemistry-led creation of a difluorinated biaryl ether non-nucleoside reverse transcriptase inhibitor.

In the process of developing a series of novel, fluorinated biaryl ether NNRTIs, we fortuitously discovered derivative 20, which possesses excellent potency against both wild-type and clinically relevant mutations of the reverse transcriptase enzyme.