David L. Brown

Design of potent inhibitors of human beta-secretase. Part 2.

We describe an optimized series of acyclic hydroxyethylamine transition state isosteres of beta-secretase that incorporates a variety of P(2) side chains that yield potent inhibitors with excellent cellular activity. A 2.2A crystal structure of compound 13 is shown.

Identification, synthesis and SAR of amino substituted pyrido(3,2b)pyrazinones as potent and selective PDE5 inhibitors

A new class of potent and selective PDE5 inhibitors is disclosed. Guided by X-ray crystallographic data, optimization of an HTS lead led to the discovery of a series of 2-aryl, (N8)-alkyl substituted-6-aminosubstituted pyrido[3,2b]pyrazinones which show potent inhibition of the PDE5 enzyme. Synthetic details and some structure-activity relationships are also presented.

Design, synthesis, and biological evaluation of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent, orally active, brain penetrant inhibitor of phosphodiesterase 5 (PDE5).

We recently described a novel series of aminopyridopyrazinones as PDE5 inhibitors. Efforts toward optimization of this series culminated in the identification of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, which possessed an excellent potency and selectivity profile and demonstrated robust in vivo blood pressure lowering in a spontaneously hypertensive rat (SHR) model. Furthermore, this compound is brain penetrant and will be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5. This compound has recently entered clinical trials.

Investigation of aminopyridiopyrazinones as PDE5 inhibitors: Evaluation of modifications to the central ring system.

Efforts to improve the potency and physical properties of the aminopyridiopyrazinone class of PDE5 inhibitors through modification of the core ring system are described. Five new ring systems are evaluated and features that impart improved potency and improved solubility are delineated.

Optimization of the aminopyridopyrazinones class of PDE5 inhibitors: discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one.

We describe efforts to improve the pharmacokinetic profile of the aminopyridopyrazinone class of PDE5 inhibitors. These efforts led to the discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent and selective inhibitor of PDE5 with an excellent PK profile.

Readout demonstration of 512 TES bolometers using a single microwave SQUID multiplexer (Conference Presentation)

To enable the next-generation of bolometric cameras, we are developing the microwave SQUID multiplexer (μMUX). Upcoming receivers such as Simons Observatory, CCAT-prime, BICEP array, Ali-CPT, and CMB-S4 plan to instrument focal planes with 50,000-500,000 sensors. Sensor count is achieved by tiling many 150 mm-diameter densely packed detector arrays into these focal planes. The fabrication and quality of large-format bolometer arrays has been demonstrated and is now mature. In contrast, the readout technology required for next-generation receivers needs development. The sensitivity, low cross-talk, high multiplexing density, and small component size make the μMUX well-suited for this goal. In this approach, the TES signal modulates the inductance of an rf-SQUID that loads a high-Q microwave resonator. The coupled signal therefore modulates the microwave resonance frequency, which may be read out using homodyne techniques. By coupling each resonator to the same microwave feedline, many detectors can be read out on a single coaxial cable pair. The multiplexing density is in practice limited by signal bandwidth, allowable cross-talk, and the digitization bandwidth of room-temperature readout electronics.nnWe present the design and performance of a scalable 64-channel multiplexer chip optimized for bolometric applications. We utilize a new quarter wave resonator design that increases the physical linear density by a factor of two, therefore achieving a smaller footprint for simplified detector packaging. Measurements of this design show 100 kHz resonator bandwidth, uniform 1.8 MHz frequency spacing, and an input referred current noise of 35 pA/√Hz that is well below the level of an optimized, background-limited TES bolometer. Using 8 daisy-chained and frequency scaled chips, we create a 512-channel multiplexer and use it to readout a 512 TES-bolometer array. We present the results of this large-scale μMUX demonstration including system yield, signal cross-talk, and an analysis of noise in various TES bias configurations. The result demonstrates the multiplexing density required to read out 2,000 sensors between 4-8 GHz.