Testing models for molecular gas formation in galaxies: hydrostatic pressure or gas and dust shielding?

Stars in galaxies form in giant molecular clouds that coalesce when the atomic hydrogen is converted into molecules. There are currently two dominant models for what property of the galactic disk determines its molecular fraction: either hydrostatic pressure driven by the gravity of gas and stars, or a combination of gas column density and metallicity. To assess the validity of these models, we compare theoretical predictions to the observed atomic gas content of low-metallicity dwarf galaxies with high stellar densities. The extreme conditions found in these systems are optimal to distinguish the two models, otherwise degenerate in nearby spirals. Locally, on scales <100 pc, we find that the state of the interstellar medium is mostly sensitive to the gas column density and metallicity rather than hydrostatic pressure. On larger scales where the average stellar density is considerably lower, both pressure and shielding models reproduce the observations, even at low metallicity. We conclude that models based on gas and dust shielding more closely describe the process of molecular formation, especially at the high resolution that can be achieved in modern galaxy simulations or with future radio/millimeter arrays.Comment: 20 pages, 12 figures. Accepted for publication in Ap

Discovery of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators with robust central efficacy† †Electronic supplementary information (ESI) available. CCDC 1452774. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6md00406g

γ-Secretase modulators for the treatment of Alzheimer's disease. Herein we describe the discovery of a novel series of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators for the treatment of Alzheimer's disease (AD). Using ligand-based design tactics such as conformational analysis and molecular modeling, a cyclopropyl chromane unit was identified as a suitable heterocyclic replacement for a naphthyl moiety that was present in the preliminary lead 4 . The optimized lead molecule 44 achieved good central exposure resulting in robust and sustained reduction of brain amyloid-β42 (Aβ42) when dosed orally at 10 mg kg –1 in a rat time-course study. Application of the unpaced isolated heart Langendorff model enabled efficient differentiation of compounds with respect to cardiovascular safety, highlighting how minor structural changes can greatly impact the safety profile within a series of compounds

Design, Synthesis, and Pharmacological Evaluation of a Novel Series of Pyridopyrazine-1,6-dione γ‑Secretase Modulators

Herein we describe the design and synthesis of a novel series of γ-secretase modulators (GSMs) that incorporates a pyridopiperazine-1,6-dione ring system. To align improved potency with favorable ADME and in vitro safety, we applied prospective physicochemical property-driven design coupled with parallel medicinal chemistry techniques to arrive at a novel series containing a conformationally restricted core. Lead compound <b>51</b> exhibited good in vitro potency and ADME, which translated into a favorable in vivo pharmacokinetic profile. Furthermore, robust reduction of brain Aβ42 was observed in guinea pig at 30 mg/kg dosed orally. Through chemical biology efforts involving the design and synthesis of a clickable photoreactive probe, we demonstrated specific labeling of the presenilin N-terminal fragment (PS1-NTF) within the γ-secretase complex, thus gaining insight into the binding site of this series of GSMs

Design of Pyridopyrazine-1,6-dione γ‑Secretase Modulators that Align Potency, MDR Efflux Ratio, and Metabolic Stability

Herein we describe the design and synthesis of a series of pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) for Alzheimer’s disease (AD) that achieve good alignment of potency, metabolic stability, and low MDR efflux ratios, while also maintaining favorable physicochemical properties. Specifically, incorporation of fluorine enabled design of metabolically less liable lipophilic alkyl substituents to increase potency without compromising the sp³-character. The lead compound <b>21</b> (PF-06442609) displayed a favorable rodent pharmacokinetic profile, and robust reductions of brain Aβ42 and Aβ40 were observed in a guinea pig time-course experiment