Pediatric otolaryngology in the United States: Chevalier Jackson's legacy for the 21st century.

Chevalier Jackson and his disciples in pediatric bronchology and esophagology strove to conquer the 3 great illnesses of the early 20th century: lye ingestion with esophageal cicatrix formation, foreign-body aspiration, and tuberculosis. Jackson's successes and legacy were based on teaching through the use of clinical drawings and his improvements in instrumentation, which have saved generations of children. Clinical specialization and meticulous teamwork protected children's airways from the ravages of diphtheria. Jackson observed the mechanics of respiratory pulmonary function and gained a better understanding of the causes of pulmonary wheezes. A recent biography, Swallow, tells of Jackson's life and his important contributions to the care of all children.

Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease.

INTRODUCTION: Inhibition of gamma-secretase presents a direct target for lowering Aß production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy. METHODS: In vitro assays monitoring inhibitor potencies at APP γ-site cleavage (equivalent to Aß40), and Notch ε-site cleavage, in conjunction with a single cell assay to simultaneously monitor selectivity for inhibition of Aß production vs. Notch signaling were developed to discover APP selective gamma-secretase inhibitors. In vivo efficacy for acute reduction of brain Aß was determined in the PDAPP transgene model of AD, as well as in wild-type FVB strain mice. In vivo selectivity was determined following seven days x twice per day (b.i.d.) treatment with 15 mg/kg/dose to 1,000 mg/kg/dose ELN475516, and monitoring brain Aß reduction vs. Notch signaling endpoints in periphery. RESULTS: The APP selective gamma-secretase inhibitors ELN318463 and ELN475516 reported here behave as classic gamma-secretase inhibitors, demonstrate 75- to 120-fold selectivity for inhibiting Aß production compared with Notch signaling in cells, and displace an active site directed inhibitor at very high concentrations only in the presence of substrate. ELN318463 demonstrated discordant efficacy for reduction of brain Aß in the PDAPP compared with wild-type FVB, not observed with ELN475516. Improved in vivo safety of ELN475516 was demonstrated in the 7d repeat dose study in wild-type mice, where a 33% reduction of brain Aß was observed in mice terminated three hours post last dose at the lowest dose of inhibitor tested. No overt in-life or post-mortem indications of systemic toxicity, nor RNA and histological end-points indicative of toxicity attributable to inhibition of Notch signaling were observed at any dose tested. CONCLUSIONS: The discordant in vivo activity of ELN318463 suggests that the potency of gamma-secretase inhibitors in AD transgenic mice should be corroborated in wild-type mice. The discovery of ELN475516 demonstrates that it is possible to develop APP selective gamma-secretase inhibitors with potential for treatment for AD.

Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: structure-activity relationship of the aryl region.

The structure-activity relationship of the prime region of hydroxyethylamine BACE inhibitors is described. Variation in the aryl linker region with 5- and 6-membered heterocycles provided compounds such as 33 with improved permeability and reduced P-gp liability compared to benzyl amine analog 1.

Improving the permeability of the hydroxyethylamine BACE-1 inhibitors: structure-activity relationship of P2' substituents.

Herein we describe further evolution of hydroxyethylamine inhibitors of BACE-1 with enhanced permeability characteristics necessary for CNS penetration. Variation at the P2' position of the inhibitor with more polar substituents led to compounds 19 and 32, which retained the potency of more lipophilic analog 1 but with much higher observed passive permeability in MDCK cellular assay.

Posterior commissure of the human larynx revisited.

The existence of the posterior commissure (PC) of the human larynx has been disputed (Hirano M, Sato K, et al. The posterior glottis. Trans Am Laryngol Assoc. 1986;107:70-75). "The term posterior commissure has no relevance to anatomical structure. The term commissure means a joining together. The bilateral vocal folds never join at their posterior ends. The posterior aspect of the glottis is a wall. The posterior lateral aspect of the posterior glottis is also the lateral wall of the posterior glottis" (Hirano M, Sato K, et al. The posterior glottis. Trans Am Laryngol Assoc. 1986;107:70-75). This study is intended to clarify the development of anatomical and morphological aspects of the PC in conjunction with a clinical classification of the larynx in sagittal view. This study uses human embryo and fetal laryngeal sections from the Carnegie Collection of Human Embryos (the world standard) and whole organ laryngeal sections from the Tucker Laryngeal Fetal Collection. Correlation of histologic and gross anatomical structure is made with the Hirano et al atlas, the Vidic Photographic Atlas of the Human Body, and the O'Rahilly Embryonic Atlas. Embryologic data clearly describe and illustrate the posterior union of the cricoid cartilage with formation of the PC. The anatomical functional aspects of the posterior lateral cricoid lamina as the supporting buttress of the articulating arytenoid cartilages are illustrated.

Design and synthesis of cell potent BACE-1 inhibitors: structure-activity relationship of P1' substituents.

Using structure-guided design, hydroxyethylamine BACE-1 inhibitors were optimized to nanomolar Abeta cellular inhibition with selectivity against cathepsin-D. X-ray crystallography illuminated the S1' residues critical to this effort, which culminated in compounds 56 and 57 that exhibited potency and selectivity but poor permeability and high P-gp efflux.

Heterobiaryl human immunodeficiency virus entry inhibitors.

Previously disclosed HIV (human immunodeficiency virus) attachment inhibitors, exemplified by BMS 806 (formally BMS378806, 1), are characterized by a substituted indole or azaindole ring linked to a benzoylpiperazine via a ketoamide or sulfonamide group. In the present report, we describe the discovery of a novel series of potent HIV entry inhibitors in which the indole or azaindole ring of previous inhibitors is replaced by a heterobiaryl group. Several of these analogues exhibited IC(50) values of less than 5 nM in a pseudotyped antiviral assay, and compound 13k was demonstrated to exhibit potency and selectivity similar to those of 1 against a panel of clinical viral isolates. Moreover, current structure-activity relationship studies of these novel biaryl gp120 inhibitors revealed that around the biaryl, a fine crevice might exist in the gp120 binding site. Taken in sum, these data reveal a hitherto unsuspected flexibility in the structure-activity relationships for these inhibitors and suggest new avenues for exploration and gp120 inhibitor design.

Design and synthesis of human immunodeficiency virus entry inhibitors: sulfonamide as an isostere for the alpha-ketoamide group.

The crystal structures of many tertiary alpha-ketoamides reveal an orthogonal arrangement of the two carbonyl groups. Based on the hypothesis that the alpha-ketoamide HIV attachment inhibitor BMS 806 (formally BMS378806, 26) might bind to its gp120 target via a similar conformation, we designed and synthesized a series of analogs in which the ketoamide group is replaced by an isosteric sulfonamide group. The most potent of these analogs, 14i, demonstrated antiviral potency comparable to 26 in the M33 pseudotyped antiviral assay. Flexible overlay calculations of a ketoamide inhibitor with a sulfonamide inhibitor revealed a single conformation of each that gave significantly better overlap of key pharmacophore features than other conformations and thus suggest a possible binding conformation for each class.

Tracheobronchial stenting in an infant with an anomalous right main bronchus.

Congenital anomalies of the right main bronchi have not been fully described. Bronchial anomalies are usually asymptomatic unless they coexist with other abnormalities. We describe a rare bronchial anomaly in a 2-month-old girl in which the right upper lobe, middle lobe, and lower lobe bronchi all originated at the same point as a result of a developmental teratogenic long right main bronchus and an absent bronchus intermedius. Furthermore, the left main bronchus contained a proximal segment of stenosis. This combination of anomalies, along with right upper lobe atelectasis and left-sided hyperinflation, resulted in a severe right mediastinal shift and respiratory distress. The mediastinum was returned to midline with endoscopic placement of an in-dwelling tracheobronchial stent into the left main bronchus. To the best of our knowledge, the specific developmental anomaly in our patient has not been previously described.

Design, synthesis, and crystal structure of hydroxyethyl secondary amine-based peptidomimetic inhibitors of human beta-secretase.

The design and synthesis of a novel series of potent and cell permeable peptidomimetic inhibitors of the human beta-secretase (BACE) are described. These inhibitors feature a hydroxyethyl secondary amine isostere and a novel aromatic ring replacement for the C-terminus. The crystal structure of BACE in complex with this hydroxyethyl secondary amine isostere inhibitor is also presented.

Broad-spectrum antiherpes activities of 4-hydroxyquinoline carboxamides, a novel class of herpesvirus polymerase inhibitors.

Through broad screening of the compound library at Pharmacia, a naphthalene carboxamide was identified as a nonnucleoside inhibitor of human cytomegalovirus (HCMV) polymerase. Structure-activity relationship studies demonstrated that a quinoline ring could be substituted for naphthalene, resulting in the discovery of a 4-hydroxyquinoline-3-carboxamide (4-HQC) class of antiviral agents with unique biological properties. In vitro assays with the 4-HQCs have demonstrated potent inhibition of HCMV, herpes simplex virus type 1 (HSV-1), and varicella-zoster virus (VZV) polymerases but no inhibition of human alpha, delta, and gamma polymerases. Antiviral cell culture assays have further confirmed that these compounds are active against HCMV, HSV-1, HSV-2, VZV, and many animal herpesviruses. However, these compounds were not active against several nonherpesviruses representing different DNA and RNA virus families. A strong correlation between the viral DNA polymerase and antiviral activity for this class of compounds supports inhibition of the viral polymerase as the mechanism of antiviral activity. Northern blot analysis of immediate-early and late viral transcripts also pointed to a block in the viral life cycle consistent with inhibition of viral DNA replication. In vitro HCMV polymerase assays indicate that the 4-HQCs are competitive inhibitors of nucleoside binding. However, no cross-resistance could be detected with ganciclovir-resistant HCMV or acyclovir-resistant HSV-1 mutants. The unique, broad-spectrum activities of the 4-HQCs may offer new opportunities for treating many of the diseases caused by herpesviruses.

Alkylation of Ketene Silyl Acetals with Nitroolefins Mediated by Sterically Encumbered Lewis Acids.

The utility of nitroolefins as "(+)C-C-NH(2)" and "(+)C(C=O)R" synthons is limited by their facile polymerization in the presence of nucleophiles. Although a number of procedures have been developed for the successful alkylation of ketones with nitroolefins, currently available procedures for the corresponding reaction of esters suffer from important limitations such as modest yields, lack of demonstrated generality, inconveniently low reaction temperatures, and/or the use of a large excess of one of the two reactants. In the present work, we examined the efficacy of a series of Lewis acid catalysts for the alkylation of ketene silyl acetals with nitroolefins. Previously reported conditions using diisopropoxytitanium dichloride failed to give satisfactory results with nitroolefins lacking a substituent alpha to the NO(2) group. In contrast, good to excellent results were obtained using sterically congested Lewis acids of the type pioneered by Yamamoto. The successful use of nitroethylene in this reaction represents a significant extension of the utility of this relatively unused "(+)CH(2)CH(2)NH(2)" synthon.