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1.
J Am Chem Soc ; 136(31): 11100-6, 2014 Aug 06.
Article in English | MEDLINE | ID: mdl-25026466

ABSTRACT

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. Our strategy utilizes a binary mixture of a relatively long and a relatively short poly(methacrylic acid) stabilizer block, which become preferentially expressed at the outer and inner poly(benzyl methacrylate) membrane surface, respectively. Dynamic light scattering was utilized to construct phase diagrams to identify suitable conditions for the synthesis of relatively small, low-polydispersity vesicles. Small-angle X-ray scattering (SAXS) was used to verify that this binary mixture approach produced vesicles with significantly narrower size distributions compared to conventional vesicles prepared using a single (short) stabilizer block. Calculations performed using self-consistent mean field theory (SCMFT) account for the preferred self-assembled structures of the block copolymer binary mixtures and are in reasonable agreement with experiment. Finally, both SAXS and SCMFT indicate a significant degree of solvent plasticization for the membrane-forming poly(benzyl methacrylate) chains.

2.
Bioorg Med Chem Lett ; 21(20): 6176-9, 2011 Oct 15.
Article in English | MEDLINE | ID: mdl-21889344

ABSTRACT

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.


Subject(s)
Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Glycine/analogs & derivatives , Animals , Glycine/chemistry , Glycine/metabolism , Glycine/pharmacokinetics , Glycine/pharmacology , Glycine Plasma Membrane Transport Proteins/metabolism , Humans , Inhibitory Concentration 50 , Rats , Solubility , Structure-Activity Relationship
3.
Bioorg Med Chem Lett ; 20(18): 5434-8, 2010 Sep 15.
Article in English | MEDLINE | ID: mdl-20709550

ABSTRACT

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.


Subject(s)
Benzoxazoles/pharmacokinetics , Indoles/pharmacokinetics , Memory Disorders/drug therapy , Muscarinic Agonists/pharmacokinetics , Nootropic Agents/pharmacokinetics , Receptor, Muscarinic M1/metabolism , Animals , Benzoxazoles/chemistry , Benzoxazoles/therapeutic use , Brain/metabolism , Indoles/chemistry , Indoles/therapeutic use , Muscarinic Agonists/chemistry , Muscarinic Agonists/therapeutic use , Nootropic Agents/chemistry , Nootropic Agents/therapeutic use , Oxindoles , Rats
4.
Bioorg Med Chem Lett ; 19(3): 837-40, 2009 Feb 01.
Article in English | MEDLINE | ID: mdl-19117759

ABSTRACT

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.


Subject(s)
Central Nervous System/drug effects , Quinolines/chemical synthesis , Receptors, Neurokinin-3/antagonists & inhibitors , Amines/metabolism , Animals , Area Under Curve , Brain/metabolism , Cerebral Cortex/embryology , Gerbillinae , Male , Models, Chemical , Quinolines/metabolism , Quinolines/pharmacology , Rats , Rats, Sprague-Dawley
5.
Bioorg Med Chem Lett ; 19(2): 428-32, 2009 Jan 15.
Article in English | MEDLINE | ID: mdl-19071020

ABSTRACT

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.


Subject(s)
Quinolines/pharmacology , Receptors, Serotonin, 5-HT1/drug effects , Administration, Oral , Animals , Biological Availability , Ligands , Quinolines/administration & dosage , Quinolines/chemistry , Quinolines/pharmacokinetics , Rats , Structure-Activity Relationship
6.
Biomaterials ; 28(35): 5319-31, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17888510

ABSTRACT

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. Subsequent co-culture of epithelial and stromal cells on the amine modified hydrogels allowed successful expansion of epithelial cells on surfaces functionalized with alkyl alpha-omega diamines with carbon chain lengths of between 3 and 6. Analysis of variance showed that corneal epithelial cells had a strong preference for surfaces functionalized by the reaction of excess 1,3 diaminopropane with units of glycidyl methacrylate compared to the reaction products of other amines (ammonia; 1,2-diaminoethane; 1,4-diaminobutane or 1,6-diaminohexane). We suggest this approach of amine functionalization combined with stromal/epithelial co-culture offers a promising new approach to achieving a secure corneal epithelium.


Subject(s)
Amines/metabolism , Cell Differentiation/physiology , Cornea/cytology , Epithelium, Corneal/cytology , Epithelium, Corneal/physiology , Hydrogels/metabolism , Models, Biological , Amines/chemistry , Animals , Cattle , Cell Communication/physiology , Cells, Cultured , Coculture Techniques , Cornea/metabolism , Epithelial Cells/chemistry , Epithelial Cells/cytology , Epithelial Cells/metabolism , Epithelium, Corneal/chemistry , Humans , Hydrogels/chemistry , Stromal Cells/chemistry , Stromal Cells/cytology , Stromal Cells/physiology
7.
Neuropharmacology ; 50(8): 984-90, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16546225

ABSTRACT

SB-616234-A possesses high affinity for human 5-HT1B receptors stably expressed in Chinese hamster ovary (CHO) cells (pKi 8.3+/-0.2), and is over 100-fold selective for a range of molecular targets except h5-HT1) receptors (pKi 6.6+/-0.1). Similarly, affinity (pKi) for rat and guinea pig striatal 5-HT1B receptors is 9.2+/-0.1. In [35S]-GTPgammaS binding studies in the human recombinant cell line, SB-616234-A acted as a high affinity antagonist with a pA2 value of 8.6+/-0.2 whilst providing no evidence of agonist activity in this system. In [35S]-GTPgammaS binding studies in rat striatal membranes, SB-616234-A acted as a high affinity antagonist with an apparent pKB of 8.4+/-0.5, again whilst providing no evidence of agonist activity in this system. SB-616234-A (1 microM) potentiated electrically stimulated [3H]-5-HT release from guinea pig and rat cortical slices (S2/S1) ratios of 1.8 and 1.6, respectively). SB-616234-A (0.3-30 mg kg(-1) p.o.) caused a dose-dependent inhibition of ex vivo [3H]-GR125743 binding to rat striatal 5-HT1B receptors with an ED50 of 2.83+/-0.39 mg kg(-1) p.o. Taken together these data suggest that SB-616234-A is a potent and selective 5-HT(1B) autoreceptor antagonist that occupies central 5-HT1B receptors in vivo following oral administration.


Subject(s)
Serotonin 5-HT1 Receptor Antagonists , Serotonin Antagonists/pharmacology , Analysis of Variance , Animals , Binding, Competitive/drug effects , CHO Cells , Cerebral Cortex/cytology , Cricetinae , Dose-Response Relationship, Drug , Drug Interactions , Electric Stimulation/methods , Guanosine 5'-O-(3-Thiotriphosphate)/pharmacokinetics , Guinea Pigs , Humans , In Vitro Techniques , Indoles/pharmacology , Membrane Potentials/drug effects , Membrane Potentials/physiology , Membrane Potentials/radiation effects , Neurons/drug effects , Neurons/physiology , Oxadiazoles/pharmacology , Patch-Clamp Techniques/methods , Piperazines/pharmacology , Protein Binding/drug effects , Rats , Serotonin/pharmacokinetics , Sulfur Isotopes/pharmacokinetics , Tritium/pharmacokinetics
8.
Proc Natl Acad Sci U S A ; 103(11): 4052-5, 2006 Mar 14.
Article in English | MEDLINE | ID: mdl-16537483

ABSTRACT

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. To evaluate the rate enhancement produced by P-O cleaving phosphodiesterases such as staphylococcal nuclease, we decided to establish the actual value of the rate constant for P-O cleavage of a simple phosphodiester anion. In dineopentyl phosphate, C-O cleavage is sterically precluded so that hydrolysis occurs only by P-O cleavage. Measurements at elevated temperatures indicate that the dineopentyl phosphate anion undergoes hydrolysis in water with a t(1/2) of 30,000,000 years at 25 degrees C, furnishing an indication of the resistance of the internucleotide linkages of DNA to water attack at phosphorus. These results imply that staphylococcal nuclease (k(cat) = 95 s(-1)) enhances the rate of phosphodiester hydrolysis by a factor of approximately 10(17). In alkaline solution, thymidylyl-3'-5'-thymidine (TpT) has been reported to decompose 10(5)-fold more rapidly than does dineopentyl phosphate. We find however that TpT and thymidine decompose at similar rates and with similar activation parameters, to a similar set of products, at pH 7 and in 1 M KOH. We infer that the decomposition of TpT is initiated by the breakdown of thymidine, not by phosphodiester hydrolysis.


Subject(s)
DNA/chemistry , Organophosphates/chemistry , Binding Sites , DNA/metabolism , Hydrogen-Ion Concentration , Hydrolysis , In Vitro Techniques , Kinetics , Micrococcal Nuclease/metabolism , Models, Molecular , Organophosphates/metabolism , Phosphorus/chemistry , Thermodynamics , Water/chemistry
9.
Bioorg Med Chem Lett ; 15(21): 4708-12, 2005 Nov 01.
Article in English | MEDLINE | ID: mdl-16153839

ABSTRACT

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.


Subject(s)
Serotonin 5-HT1 Receptor Antagonists , Serotonin Antagonists/chemical synthesis , Animals , Humans , Ligands , Microsomes, Liver , Rats , Serotonin Antagonists/pharmacology , Structure-Activity Relationship
10.
Bioorg Med Chem Lett ; 14(14): 3631-4, 2004 Jul 16.
Article in English | MEDLINE | ID: mdl-15203132

ABSTRACT

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. Study of a quaternary salt of 5 supports a mode of action in which compounds from this series cause inhibition via an extracellularly accessible binding site on the TRPV1 receptor.


Subject(s)
Aminobiphenyl Compounds/pharmacology , Receptors, Drug/antagonists & inhibitors , Animals , Binding Sites , Calcium/analysis , Calcium/metabolism , Capsaicin/analogs & derivatives , Capsaicin/pharmacology , Cell Line , Electrophysiology , Fluorescence , Hot Temperature , Humans , Hydrogen-Ion Concentration , Image Enhancement , Patch-Clamp Techniques , Rats , Receptors, Drug/chemistry , Structure-Activity Relationship , TRPV Cation Channels
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