- Synthesis of 11C-labeled Sulfonyl Carbamates through a Multicomponent Reaction Employing Sulfonyl Azides, Alcohols, and [11C]CO
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We describe the development of a new methodology focusing on 11C-labeling of sulfonyl carbamates in a multicomponent reaction comprised of a sulfonyl azide, an alkyl alcohol, and [11C]CO. A number of 11C-labeled sulfonyl carbamates were synthesized and isolated, and the developed methodology was then applied in the preparation of a biologically active molecule. The target compound was obtained in 24±10 % isolated radiochemical yield and was evaluated for binding properties in a tumor cell assay; in vivo biodistribution and imaging studies were also performed. This represents the first successful radiolabeling of a non-peptide angiotensin II receptor subtype 2 agonist, C21, currently in clinical trials for the treatment of idiopathic pulmonary fibrosis.
- Stevens, Marc Y.,Chow, Shiao Y.,Estrada, Sergio,Eriksson, Jonas,Asplund, Veronika,Orlova, Anna,Mitran, Bogdan,Antoni, Gunnar,Larhed, Mats,?berg, Ola,Odell, Luke R.
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- Single Peptide Backbone Surrogate Mutations to Regulate Angiotensin GPCR Subtype Selectivity
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Mutating the side-chains of amino acids in a peptide ligand, with unnatural amino acids, aiming to mitigate its short half-life is an established approach. However, it is hypothesized that mutating specific backbone peptide bonds with bioisosters can be exploited not only to enhance the proteolytic stability of parent peptides, but also to tune its receptor subtype selectivity. Towards this end, four [Y]6-Angiotensin II analogues are synthesized where amide bonds have been replaced by 1,4-disubstituted 1,2,3-triazole isosteres in four different backbone locations. All the analogues possessed enhanced stability in human plasma in comparison with the parent peptide, whereas only two of them achieved enhanced AT2R/AT1R subtype selectivity. This diversification has been studied through 2D NMR spectroscopy and unveiled a putative more structured microenvironment for the two selective ligands accompanied with increased number of NOE cross-peaks. The most potent analogue, compound 2, has been explored regarding its neurotrophic potential and resulted in an enhanced neurite growth with respect to the established agent C21.
- Vrettos, Eirinaios I.,Valverde, Ibai E.,Mascarin, Alba,Pallier, Patrick N.,Cerofolini, Linda,Fragai, Marco,Parigi, Giacomo,Hirmiz, Baydaa,Bekas, Nick,Grob, Nathalie M.,Stylos, Evgenios Κ.,Shaye, Hamidreza,Del Borgo, Mark,Aguilar, Marie-Isabel,Magnani, Francesca,Syed, Nelofer,Crook, Timothy,Waqif, Emal,Ghazaly, Essam,Cherezov, Vadim,Widdop, Robert E.,Luchinat, Claudio,Michael-Titus, Adina T.,Mindt, Thomas L.,Tzakos, Andreas G.
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supporting information
p. 10690 - 10694
(2020/07/25)
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- A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode
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We here report on our continued studies of ligands binding to the promising drug target angiotensin II type 2 receptor (AT2R). Two series of compounds were synthesized and investigated. The first series explored the effects of adding small subs
- Isaksson, Rebecka,Lindman, Jens,Wannberg, Johan,Sallander, Jessica,Backlund, Maria,Baraldi, Dhaniel,Widdop, Robert,Hallberg, Mathias,?qvist, Johan,Gutierrez de Teran, Hugo,Gising, Johan,Larhed, Mats
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p. 114 - 125
(2019/02/07)
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- A convenient transesterification method for synthesis of AT2 receptor ligands with improved stability in human liver microsomes
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A series of AT2R ligands have been synthesized applying a quick, simple, and safe transesterification-type reaction whereby the sulfonyl carbamate alkyl tail of the selective AT2R antagonist C38 was varied. Furthermore, a limited number of compounds where acyl sulfonamides and sulfonyl ureas served as carboxylic acid bioisosteres were synthesized and evaluated. By reducing the size of the alkyl chain of the sulfonyl carbamates, ligands 7a and 7b were identified with significantly improved in vitro metabolic stability in both human and mouse liver microsomes as compared to C38 while retaining the AT2R binding affinity and AT2R/AT1R selectivity. Eight of the compounds synthesized exhibit an improved stability in human microsomes as compared to C38.
- Wannberg, Johan,Isaksson, Rebecka,Bremberg, Ulf,Backlund, Maria,S?vmarker, Jonas,Hallberg, Mathias,Larhed, Mats
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p. 519 - 522
(2018/01/04)
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- NEW TRICYCLIC ANGIOTENSIN II AGONISTS
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There is provided compounds of formula (I) wherein the dotted line, X1, X2, X3, A, Y1, Y2, Y3, Y4, Z1, Z2, R2 and R3 have meanings giv
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Page/Page column 32-33
(2008/06/13)
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- NEW BICYCLIC ANGIOTENSIN II AGONISTS
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There is provided a compound of formula (I) wherein R1a, R1b, X, Y1, Y2, Y3, Y4, Z1, Z2, R2 and R3 have meanings given in the description, and ph
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Page/Page column 36
(2008/06/13)
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- NEW TRICYCLIC ANGIOTENSIN II AGONISTS
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There is provided compounds of Formula (I), wherein A, X1, X2, X3, X4, Y1, Y2, Y3, Y4, Z1, Z2, R4 and R5 have meanings given in the description, and pharmaceuticalfy-acceptable salts thereof, which compounds are useful as selective agonists of the AT2 receptor, and thus, in particular, in the treatment of inter alia gastrointestinal conditions, such as dyspepsia, IBS and MOF, and cardiovascular disorders.
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Page/Page column 35-36
(2008/06/13)
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- NEW TRICYCLIC ANGIOTENSIN II AGONISTS
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There is provided compounds of formula (I), wherein the dotted lines, XI, X2, X3, X4, A, YI, Y2, Y3, Y4, ZI, Z2, R2 and R3
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- NEW BICYCLIC ANGIOTENSIN II AGONISTS
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There is provided compounds of formula (I), wherein R1a, R1b, n, Y1, Y2, Y3, Y4, Z1, Z2, R2 and R3 have meanings given in the description, and pharmaceutically-acceptable salts thereof, which compounds are useful as selective agonists of the AT2 receptor, and thus, in particular, in the treatment of inter alia gastrointestinal conditions, such as dyspepsia, IBS and MOF, and cardiovascular disorders.
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- NEW TRICYCLIC ANGIOTENSIN II AGONISTS
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There is provided compounds of formula (I), wherein the dotted line, X1, X2, X3, A, Y1, Y2, Y3, Y4, Z1, Z2, R2 and R3 have meanings gi
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- BICYCLIC COMPOUNDS USEFUL AS ANGIOTENSIN II AGONISTS
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There is provided compounds of formula I, wherein R1a, R1b, X, Y1, Y2, Y3, Y4, Z 1, Z2, R2 and R3 have meanings given in the description, and pha
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- Pharmaceutical treatment methods using angiotensin II receptor agonists bearing a thiophene moiety
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This invention relates to compounds represented by formula I: STR1 which are agonists of angiotensin II. The invention is also concerned with the use of aforementioned agonists in the treatment of states meditated by angiotensin.
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