Serotonin 5-HT4 Agonist Activity of a Series of Meso-Azanoradamantane Benzamides

A series of meso-amino(methyl)azanoradamantane benzamides has been prepared and evaluated for 5-HT4agonism activity in the rat tunica muscularis mucosae (TMM) assay. Compound 8i is the most potent 5-HT4agonist in the series, with an EC50 of 217 nM

Synthetic Strategies for the Construction of Enantiomeric Azanoradamantanes

The amino azanoradamantane hexahydro-2,5b-methano-IH-3aS,3aa,6aa-cyclopenta-[clpyrrole-4a-amine 1and the corresponding enantiomer ent-1 have been prepared along with benzamide derivatives SC-52491and SC-52490, respectively, which are of pharmaceutical interest. The key meso-azabicyclo[3.3.0] intermediate 3 was prepared via three separate routes: a [3+2] cycloaddition route, a radical cyclization/ionic cyclization route, and a reductive Pauson-Khand route

Innovation and continuous improvement in a seemingly accelerated regulatory environment Roger Nosal, Pfizer Inc

Biopharmaceutical innovation can improve quality assurance, manufacturing capacity & process efficiency. However global regulatory trends are a barrier to continuous improvement and acceleration only exacerbates product development. While several recent draft guidelines & initiatives1-3 portend to enable innovation, in practice, regulatory expectations reflect increasingly punitive rather than incentive-based opportunities: • Redundant downstream justification for upstream changes, i.e., stability • Submission of GMP/supply chain information for review • Misaligned regulatory review & inspection • Global regulatory divergence – RSMs, viral clearance, PACs This presentation describes manufacturing innovations in the context of increasing regulatory demands & under accelerated development timelines. 1Assay Development & Validation for Immunogenicity Testing of Therapeutic Protein Products, Draft Guidance for Industry, FDA/CDER, CBER & CDRH, April 2016. 2Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base, Draft Guidance for Industry, FDA/CDER, December 2015. 3Established Conditions: Reportable CMC Changes for Drug and Biologic Products, Draft Guidance for Industry, FDA/CDER & CBER, May 2015

Wind, waves, and acoustic background levels at Station ALOHA

Author Posting. © American Geophysical Union, 2012. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 117 (2012): C03017, doi:10.1029/2011JC007267.Frequency spectra from deep-ocean near-bottom acoustic measurements obtained contemporaneously with wind, wave, and seismic data are described and used to determine the correlations among these data and to discuss possible causal relationships. Microseism energy appears to originate in four distinct regions relative to the hydrophone: wind waves above the sensors contribute microseism energy observed on the ocean floor; a fraction of this local wave energy propagates as seismic waves laterally, and provides a spatially integrated contribution to microseisms observed both in the ocean and on land; waves in storms generate microseism energy in deep water that travels as seismic waves to the sensor; and waves reflected from shorelines provide opposing waves that add to the microseism energy. Correlations of local wind speed with acoustic and seismic spectral time series suggest that the local Longuet-Higgins mechanism is visible in the acoustic spectrum from about 0.4 Hz to 80 Hz. Wind speed and acoustic levels at the hydrophone are poorly correlated below 0.4 Hz, implying that the microseism energy below 0.4 Hz is not typically generated by local winds. Correlation of ocean floor acoustic energy with seismic spectra from Oahu and with wave spectra near Oahu imply that wave reflections from Hawaiian coasts, wave interactions in the deep ocean near Hawaii, and storms far from Hawaii contribute energy to the seismic and acoustic spectra below 0.4 Hz. Wavefield directionality strongly influences the acoustic spectrum at frequencies below about 2 Hz, above which the acoustic levels imply near-isotropic surface wave directionality.Funding for the ALOHA Cabled Observatory was provided by the National Science Foundation and the State of Hawaii through the School of Ocean and Earth Sciences and Technology at the University of Hawaii-Manoa (F. Duennebier, PI). Donations from AT&T and TYCOM and the cooperation of the U.S. Navy made this project possible. The WHOI-Hawaii Ocean Time series Station (WHOTS) mooring is maintained by Woods Hole Oceanographic Institution (PIs R. Weller and A. Plueddemann) with funding from the NOAA Climate Program Office/Climate Observation Division. NSF grant OCE- 0926766 supported R. Lukas (co-PI) to augment and collaborate on the maintenance of WHOTS. Lukas was also supported during this analysis by The National Ocean Partnership Program “Advanced Coupled Atmosphere-Wave-Ocean Modeling for Improving Tropical Cyclone Prediction Models” under contract N00014-10-1-0154 to the University of Rhode Island (I. Ginis, PI).2012-09-1

Use of Atom-transfer Radical Cyclizations as an Efficient Entry into a New Serotonergic Norazaadamantane

A route to azanoradamantanes is described which makes use of an atom-transfer radical cyclization to afford 3-azabicyclo[3.3.0]octanes 3A and 3B. Subsequent elaboration of exo-allylamine functionality, followed by cyclization of the endo-hydroxymethyl intermediate 9, affords the new azanoradamantanes 11 and 4. This new azatricyclic system is useful for producing serotonin 5-HT3 antagonists and 5-HT4 agonists