Rational synthesis of low-polydispersity block copolymer vesicles in concentrated solution via polymerization-induced self-assembly.

Block copolymer self-assembly is normally conducted via post-polymerization processing at high dilution. In the case of block copolymer vesicles (or "polymersomes"), this approach normally leads to relatively broad size distributions, which is problematic for many potential applications. Herein we report the rational synthesis of low-polydispersity diblock copolymer vesicles in concentrated solution via polymerization-induced self-assembly using reversible addition-fragmentation chain transfer (RAFT) polymerization of benzyl methacrylate.

Acylglycinamides as inhibitors of glycine transporter type 1.

A screening hit was used as the basis for the core structure of a new series of acylglycinamide GlyT-1 inhibitors. Investigation of the SAR around four areas of diversity used facile chemistry to prepare compounds quickly. By focussing on reducing the lipophilicity and improving the aqueous solubility in the series we were able to prepare a compound (17e) with a good level of activity at GlyT-1, selectivity over GlyT-2 and moderate oral bioavailability.

The discovery of a series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles as highly brain penetrant, selective muscarinic M1 agonists.

A series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles are reported which were found to be potent and selective muscarinic M1 agonists. By control of the physicochemical characteristics of the series, particularly the lipophilicity, compounds with good metabolic stability and excellent brain penetration were identified. An exemplar of the series was shown to be pro-cognitive in the novel object recognition rat model of temporal induced memory deficit.

New quinoline NK3 receptor antagonists with CNS activity.

Lead optimisation starting from the previously reported selective quinoline NK(3) receptor antagonists talnetant 2 (SB-223412) and 3 (SB-222200) led to the identification of 3-aminoquinoline NK(3) antagonist 10 (GSK172981) with excellent CNS penetration. Investigation of a structurally related series of sulfonamides with reduced lipophilicity led to the discovery of 20 (GSK256471). Both 10 and 20 are high affinity, potent NK(3) receptor antagonists which despite having different degrees of CNS penetration produced excellent NK(3) receptor occupancy in an ex vivo binding study in gerbil cortex.

Studies on a series of potent, orally bioavailable, 5-HT(1) receptor ligands--part II.

A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different in vitro pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.

Epithelialization of hydrogels achieved by amine functionalization and co-culture with stromal cells.

The aim of this study was to develop a hydrogel which would be suitable for corneal cell re-epithelialization when used as a corneal implant. To achieve this, a series of hydrogels were functionalized with primary amines by post-polymerization reactions between amine compounds and glycidyl ether groups attached to the hydrogels. We report a strong correlation between the structure of the amine and the viability of stromal cells and epithelial cells cultured on these hydrogels.

The time required for water attack at the phosphorus atom of simple phosphodiesters and of DNA.

Phosphodiester linkages, including those that join the nucleotides of DNA, are highly resistant to spontaneous hydrolysis. The rate of water attack at the phosphorus atom of phosphodiesters is known only as an upper limit, based on the hydrolysis of the dimethyl phosphate anion. That reaction was found to proceed at least 99% by C-O cleavage, at a rate suggesting an upper limit of 10(-15) s(-1) for P-O cleavage of phosphodiester anions at 25 degrees C.

Identification of a potent and selective 5-HT1B receptor antagonist.

An SAR study around the mixed 5-HT1ABD receptor antagonist SB-272183 found that introduction of cis-2,6-dimethyl substitution onto the piperazine ring was a key structural change, which imparted a combination of both excellent selectivity over the 5-HT1A and 5-HT1D receptors and low intrinsic activity. This led to the identification of the selective 5-HT1B receptor antagonist SB-616234.

Discovery of small molecule antagonists of TRPV1.

Small molecule antagonists of the vanilloid receptor 1 (TRPV1, also known as VR1) are disclosed. Ureas such as 5 (SB-452533) were used to explore the structure activity relationship with several potent analogues identified. Pharmacological studies using electrophysiological and FLIPR Ca(2+) based assays showed compound 5 was an antagonist versus capsaicin, noxious heat and acid mediated activation of TRPV1.