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Minor Structural Change to Tertiary Sulfonamide RORc Ligands Led to Opposite Mechanisms of Action.

ABSTRACT: A minor structural change to tertiary sulfonamide RORc ligands led to distinct mechanisms of action. Co-crystal structures of two compounds revealed mechanistically consistent protein conformational changes. Optimized phenylsulfonamides were identified as RORc agonists while benzylsulfonamides exhibited potent inverse agonist activity. Compounds behaving as agonists in our biochemical assay also gave rise to an increased production of IL-17 in human PBMCs whereas inverse agonists led to significant suppression of IL-17 under the same assay conditions. The most potent inverse agonist compound showed >180-fold selectivity over the ROR isoforms as well as all other nuclear receptors that were profiled.

SUBMITTER: Rene O

PROVIDER: S-EPMC4360161 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Minor Structural Change to Tertiary Sulfonamide RORc Ligands Led to Opposite Mechanisms of Action.

René Olivier O Fauber Benjamin P BP Boenig Gladys de Leon Gde L Burton Brenda B Eidenschenk Céline C Everett Christine C Gobbi Alberto A Hymowitz Sarah G SG Johnson Adam R AR Kiefer James R JR Liimatta Marya M Lockey Peter P Norman Maxine M Ouyang Wenjun W Wallweber Heidi A HA Wong Harvey H

ACS medicinal chemistry letters 20141204 3

A minor structural change to tertiary sulfonamide RORc ligands led to distinct mechanisms of action. Co-crystal structures of two compounds revealed mechanistically consistent protein conformational changes. Optimized phenylsulfonamides were identified as RORc agonists while benzylsulfonamides exhibited potent inverse agonist activity. Compounds behaving as agonists in our biochemical assay also gave rise to an increased production of IL-17 in human PBMCs whereas inverse agonists led to signific ...[more]

PMID: 25815138

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Project description:Tertiary sulfonamide nitrogen-to-metal bonds of normal length are very rare. We recently discovered such a bond in one class of fac-[Re(CO)3(N(SO2R)(CH2Z)2)](n) complexes (Z = 2-pyridyl) with N(SO2R)dpa ligands derived from di-(2-picolyl)amine (N(H)dpa). fac-[M(CO)3(N(SO2R)(CH2Z)2)](n) agents (M = (186/188)Re, (99m)Tc) could find use as radiopharmaceutical bioconjugates when R is a targeting moiety. However, the planar, electron-withdrawing 2-pyridyl groups of N(SO2R)dpa destabilize the ligand to base and create relatively rigid chelate rings, raising the possibility that the rare M-N(sulfonamide) bond is an artifact of a restricted geometry. Also, the hydrophobic 2-pyridyl groups could cause undesirable accumulation in the liver, limiting future use in radiopharmaceuticals. Our goal is to identify a robust, hydrophilic, and flexible N(CH2Z)2 chelate framework. New C2-symmetric ligands, N(SO2R)(CH2Z)2 with (Z = CH2NH2; R = Me, dmb, or tol), were prepared by treating N(H)dien(Boc)2, a protected diethylenetriamine (N(H)dien) derivative, with methanesulfonyl chloride (MeSO2Cl), 3,5-dimethylbenzenesulfonyl chloride (dmbSO2Cl), and 4-methylbenzenesulfonyl chloride (tolSO2Cl). Treatment of fac-[Re(CO)3(H2O)3](+) with these ligands, designated as N(SO2R)dien, afforded new fac-[Re(CO)3(N(SO2R)dien)]PF6 complexes. Comparing the fac-[Re(CO)3(N(SO2Me)dien)]PF6 and fac-[Re(CO)3(N(SO2Me)dpa)]PF6 complexes, we find that the Re(I)-N(sulfonamide) bonds are normal in length and statistically identical and that the methyl (13)C NMR signal has an unusually upfield shift compared to that in the free ligand. We attribute this unusual upfield shift to the fact that the sulfonamide N undergoes an sp(2)-to-sp(3) rehybridization upon coordination to Re(I) in both complexes. Thus, the sulfonamide N of N(SO2R)dien ligands is a good donor, even though the chelate rings are conformationally flexible. Addition of the strongly basic and potentially monodentate ligand, 4-dimethylaminopyridine, did not affect the fac-[Re(CO)3(N(SO2tol)dien)]PF6 complex, even after several weeks. This complex is also stable to heat in aqueous solution. These results indicate that N(SO2R)dien ligands form fac-[Re(CO)3(N(SO2R)dien)]PF6 complexes sufficiently robust to be utilized for radiopharmaceutical development.

Project description:BackgroundCommunity pharmacies provide an appropriate setting to deliver minor ailment services (MASs). Many community pharmacy services have been developed previously without stakeholder involvement. As a result, implementation of services may fail to produce the expected impact. The aim of this research was to co-design and test the feasibility of an Australian MAS for minor ailment presentations.MethodsThis study used co-design methodology which included two phases: (1) a focus group with stakeholders to allow the conceptualization of the service and agreement on service elements; (2) a literature review of clinical guidelines and three working meetings with a team of editors and general practitioners for the development of treatment pathways. Following this, a study evaluating the feasibility of the co-designed service was undertaken. The qualitative part of the methodology associated with the feasibility study comprised semi-structured interviews with MAS pharmacists, observation and completion of a tool by change facilitators identifying barriers and facilitators to service delivery. Qualitative data obtained for all phases were analysed using thematic analysis.ResultsThe developed service included the following components: (i) an in-pharmacy consultation between the patient and pharmacist, (ii) treatment pathways accessible to pharmacists on the internet to guide consultations, (iii) existing digital communication systems used by general practice to exchange patient information, (iv) training, and (v) change facilitation. As a result of feasibility testing, twenty-six implementation factors were identified for practice change, with the main change being the simplification of the pharmacist-patient consultation and data collection processes.ConclusionsAn Australian MAS was generated as a result of co-design, while testing revealed that the co-designed service was feasible. As a result of integrating the views of multiple stakeholders, the designed MAS has been adapted to suit healthcare practices, which may increase the acceptance and impact of MAS when implemented into practice.

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Minor Structural Change to Tertiary Sulfonamide RORc Ligands Led to Opposite Mechanisms of Action.

Publications

Minor Structural Change to Tertiary Sulfonamide RORc Ligands Led to Opposite Mechanisms of Action.

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