Design and pharmacological evaluation of PF-4840154, a non-electrophilic reference agonist of the TrpA1 channel.

TrpA1 is an ion channel involved in nociceptive and inflammatory pain. It is implicated in the detection of chemical irritants through covalent binding to a cysteine-rich intracellular region of the protein. While performing an HTS of the Pfizer chemical collection, a class of pyrimidines emerged as a non-reactive, non-covalently binding family of agonists of the rat and human TrpA1 channel. Given the issues identified with the reference agonist Mustard Oil (MO) in screening, a new, non-covalently binding agonist was optimized and proved to be a superior agent to MO for screening purposes. Compound 16a (PF-4840154) is a potent, selective agonist of the rat and human TrpA1 channel and elicited TrpA1-mediated nocifensive behaviour in mouse.

On the variations of acoustic absorption peak with particle velocity in micro-perforated panels at high level of excitation.

The acoustic behavior of micro-perforated panels (MPP) is studied theoretically and experimentally at high level of pressure excitation. A model based on Forchheimer's regime of flow velocity in the perforations is proposed. This model is valid at relatively high Reynolds numbers and low Mach numbers. The experimental method consists in measuring the acoustical pressure at three different positions in an impedance tube, the two measurement positions usually considered in an impedance tube and one measurement in the vicinity of the rear surface of the MPP. The impedance tube is equipped with a pressure driver instead of the usual loudspeaker and capable of delivering a high sound pressure level up to 160 dB. MPP specimens made out of steel, dural and polypropylene were tested. Measurements using random noise or sinusoidal excitation in a frequency range between 200 and 1600 Hz were carried out on MPPs backed by air cavities. It was observed that the maximum of absorption can be a positive or a negative function of the flow velocity in the perforations. This suggests the existence of a maximum of absorption as a function of flow velocity. This behavior was predicted by the model and confirmed experimentally.

Novel indazole non-nucleoside reverse transcriptase inhibitors using molecular hybridization based on crystallographic overlays.

A major problem associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of HIV is their lack of resilience to mutations in the reverse transcriptase (RT) enzyme. Using structural overlays of the known inhibitors efavirenz and capravirine complexed in RT as a starting point, and structure-based drug design techniques, we have created a novel series of indazole NNRTIs that possess excellent metabolic stability and mutant resilience.