Cell polarity: Scaffold proteins par excellence

Par proteins are involved in determining cellular asymmetry. Recent studies have identified one of these proteins, Par6, as a key regulator of cell polarity and transformation via its interactions with small GTPases and atypical forms of protein kinase C.

Fabrication and Repair of Cartilage Defects with a Novel Acellular Cartilage Matrix Scaffold

The objectives of this study were to develop a three-dimensional acellular cartilage matrix (ACM) and investigate its possibility for use as a scaffold in cartilage tissue engineering. Bovine articular cartilage was decellularized sequentially with trypsin, nuclease solution, hypotonic buffer, and Triton x 100 solution; molded with freeze-drying process; and cross-linked by ultraviolet irradiation. Histological and biochemical analysis showed that the ACM was devoid of cells and still maintained the collagen and glycosaminoglycan components of cartilage. Scanning electronic microscopy and mercury intrusion porosimetry showed that the ACM had a sponge-like structure of high porosity. The ACM scaffold had good biocompatibility with cultured rabbit bone marrow mesenchymal stem cells with no indication of cytotoxicity both in contact and in extraction assays. The cartilage defects repair in rabbit knees with the mesenchymal stem cell-ACM constructs had a significant improvement of histological scores when compared to the control groups at 6 and 12 weeks. In summary, the ACM possessed the characteristics that afford it as a potential scaffold for cartilage tissue engineering.

Synthesis and SAR of centrally active mGlu(5) positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold

This Letter describes the hit-to-lead progression and SAR of a series of biphenyl acetylene compounds derived from an HTS screening campaign targeting the mGlu(5) receptor. 'Molecular switches' were identified that modulated modes of pharmacology, and several compounds within this series were shown to be efficacious in reversal of amphetamine induced hyperlocomotion in rats after ip dosing, a preclinical model that shows similar positive effects with known antipsychotic agents. Published by Elsevier Ltd.

Re-exploration of the PHCCC Scaffold: Discovery of Improved Positive Allosteric Modulators of mGluR4

This paper describes a detailed structure activity relationship (SAR) analysis of the metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulator, (-)-N-phenyl-7-(hydroxyimino)cyclopropa[b]-chromen-la-carboxamide (PHCCC). We have now developed compounds with improved potency and efficacy; in addition, compounds are presented that show selectivity for mGluR4 versus the other mGluR subtypes.

Discovery and SAR of a novel series of non-MPEP site mGlu(5) PAMs based on an aryl glycine sulfonammide scaffold

Herein we report the discovery and SAR of a novel series of non-MPEP site metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) based on an aryl glycine sulfonamide scaffold. This series represents a rare non-MPEP site mGlu(5) PAM chemotype.

Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 2: Development of a [3.3.0]-based series and other piperidine bioisosteres

This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach, in lieu of an HTS campaign, which provided intellectual property position. Members within this new [3.3.0]​-​based series, e.g. I, displayed excellent GlyT1 potency, selectivity, free fraction, and modest CNS penetration. Moreover, enantioselective GlyT1 inhibition was obsd., within this novel series and a no. of other piperidine bioisosteric cores.

Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 1: Development of a potent and CNS penetrant [3.1.0]-based lead

This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach that provided a robust intellectual property position, in lieu of a traditional, expensive HTS campaign. Members within this new [3.1.0]​-​based series displayed excellent GlyT1 potency, selectivity, free fraction, CNS penetration and efficacy in a preclin. model of schizophrenia (prepulse inhibition)​.

Novel free fatty acid receptor 1 (GPR40) agonists based on 1,3,4-thiadiazole-2-carboxamide scaffold

Free fatty acid receptor 1 (FFA1), previously known as GPR40 is a G protein-coupled receptor and a new target for treatment of type 2 diabetes. Two series of FFA1 agonists utilizing a 1,3,4-thiadiazole-2-caboxamide scaffold were synthetized. Both series offered significant improvement of the potency compared to the previously described 1,3,4-thiadiazole-based FFA1 agonists and high selectivity for FFA1. Molecular docking predicts new aromatic interactions with the receptor that improve agonist potency. The most potent compounds from both series were profiled for in vitro ADME properties (plasma and metabolic stability, LogD, plasma protein binding, hERG binding and CYP inhibition). One series suffered very rapid degradation in plasma and in presence of mouse liver microsomes. However, the other series delivered a lead compound that displayed a reasonable ADME profile together with the improved FFA1 potency.