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Smith, Brad

Publications and source records attributed to Smith, Brad.

5 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

Structure-Based Design of an Iminoheterocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates

We describe successful efforts to optimize the in vivo profile and address off-target liabilities of a series of BACE1 inhibitors represented by 6 that embodies the recently validated fused pyrrolidine iminopyrimidinone scaffold. Employing structure-based design, truncation of the cyanophenyl group of 6 that binds in the S3 pocket of BACE1 followed by modification of the thienyl group in S1 was pursued. Optimization of the pyrimidine substituent that binds in the S2'–S2'' pocket of BACE1 remediated time-dependent CYP3A4 inhibition of earlier analogues in this series and imparted high BACE1 affinity. These efforts resulted in the discovery of difluorophenyl analogue 9 (MBi-4), which robustly lowered CSF and cortex Aβ40 in both rats and cynomolgus monkeys following a single oral dose. Compound 9 represents a unique molecular shape among BACE inhibitors reported to potently lower central Aβ in nonrodent preclinical species.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
NASA NTRS1986

Block 2 SRM conceptual design studies. Volume 1, Book 1: Conceptual design package

The conceptual design studies of a Block 2 Solid Rocket Motor (SRM) require the elimination of asbestos-filled insulation and was open to alternate designs, such as case changes, different propellants, modified burn rate - to improve reliability and performance. Limitations were placed on SRM changes such that the outside geometry should not impact the physical interfaces with other Space Shuttle elements and should have minimum changes to the aerodynamic and dynamic characteristics of the Space Shuttle vehicle. Previous Space Shuttle SRM experience was assessed and new design concepts combined to define a valid approach to assured flight success and economic operation of the STS. Trade studies, preliminary designs, analyses, plans, and cost estimates are documented.

Smith, Brad↗