49600-34-2Relevant academic research and scientific papers
2-Aminothiazoles with Improved Pharmacotherapeutic Properties for Treatment of Prion Disease
Li, Zhe,Silber, B. Michael,Rao, Satish,Gever, Joel R.,Bryant, Clifford,Gallardo-Godoy, Alejandra,Dolghih, Elena,Widjaja, Kartika,Elepano, Manuel,Jacobson, Matthew P.,Prusiner, Stanley B.,Renslo, Adam R.
, p. 847 - 857 (2013/08/25)
Recently, we described the aminothiazole lead (4-biphenyl-4-ylthiazol-2-yl)-(6-methylpyridin-2-yl)-amine (1), which exhibits many desirable properties, including excellent stability in liver microsomes, oral bioavailability of ～40%, and high exposure in the brains of mice. Despite its good pharmacokinetic properties, compound 1 exhibited only modest potency in mouse neuroblastoma cells overexpressing the disease-causing prion protein PrPSc. Accordingly, we sought to identify analogues of 1 with improved antiprion potency in ScN2a-cl3 cells while retaining similar or superior properties. Herein we report the discovery of improved lead compounds such as (6-methylpyridin-2-yl)-[4-(4-pyridin-3-yl-phenyl)thiazol-2-yl]amine and cyclopropanecarboxylic acid (4-biphenylthiazol-2-yl)amide, which exhibit brain exposure/EC50 ratios at least tenfold greater than that of compound 1.
Structure-activity relationships of 2-aminothiazoles effective against Mycobacterium tuberculosis
Meissner, Anja,Boshoff, Helena I.,Vasan, Mahalakshmi,Duckworth, Benjamin P.,Barry III, Clifton E.,Aldrich, Courtney C.
, p. 6385 - 6397 (2013/10/22)
A series of 2-aminothiazoles was synthesized based on a HTS scaffold from a whole-cell screen against Mycobacterium tuberculosis (Mtb). The SAR shows the central thiazole moiety and the 2-pyridyl moiety at C-4 of the thiazole are intolerant to modification. However, the N-2 position of the aminothiazole exhibits high flexibility and we successfully improved the antitubercular activity of the initial hit by more than 128-fold through introduction of substituted benzoyl groups at this position. N-(3-Chlorobenzoyl)-4-(2-pyridinyl) -1,3-thiazol-2-amine (55) emerged as one of the most promising analogues with a MIC of 0.024 μM or 0.008 μg/mL in 7H9 media and therapeutic index of nearly ～300. However, 55 is rapidly metabolized by human liver microsomes (t1/2 = 28 min) with metabolism occurring at the invariant aminothiazole moiety and Mtb develops spontaneous low-level resistance with a frequency of ～10-5.
NOVEL ANTIPRION COMPOUNDS
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, (2013/03/28)
Described herein are novel compositions and methods of treatment addressing diseases such as neurodegenerative diseases, including prion diseases and Alzheimer's disease.
2-aminothiazoles as therapeutic leads for prion diseases
Gallardo-Godoy, Alejandra,Gever, Joel,Fife, Kimberly L.,Silber, B. Michael,Prusiner, Stanley B.,Renslo, Adam R.
experimental part, p. 1010 - 1021 (2011/04/25)
2-Aminothiazoles are a new class of small molecules with antiprion activity in prion-infected neuroblastoma cell lines (J. Virol. 2010, 84, 3408). We report here structure-activity studies undertaken to improve the potency and physiochemical properties of 2-aminothiazoles, with a particular emphasis on achieving and sustaining high drug concentrations in the brain. The results of this effort include the generation of informative structure-activity relationships (SAR) and the identification of lead compounds that are orally absorbed and achieve high brain concentrations in animals. The new aminothiazole analogue (5-methylpyridin-2-yl)-[4-(3-phenylisoxazol-5-yl)-thiazol-2-yl]-amine (27), for example, exhibited an EC50 of 0.94 μM in prion-infected neuroblastoma cells (ScN2a-cl3) and reached a concentration of ～25 μM in the brains of mice following three days of oral administration in a rodent liquid diet. The studies described herein suggest 2-aminothiazoles as promising new leads in the search for effective therapeutics for prion diseases.
New imidazoline/α2-adrenoceptors affecting compounds-4(5)-(2-aminoethyl)imidazoline (dihydrohistamine) derivatives. Synthesis and receptor affinity studies
Treder, Adam P.,Andruszkiewicz, Ryszard,Zgoda, W?odzimierz,Walkowiak, Aleksandra,Ford, Celeste,Hudson, Alan L.
scheme or table, p. 156 - 167 (2011/03/18)
Compilation of agmatine structure and imidazoline moiety leads to a new group of imidazoline/α2-adrenoceptor ligands, 4(5)-(2-aminoethyl)imidazoline derivatives. In this study the exploration of previously unknown 4(5)-(2-aminoethyl)imidazolines including the analogues of reported imidazoline and α2-aderenoceptors ligands: clonidine, rilmenidine, idazoxan, efaroxan, antazoline, tracizoline is described. The synthesis of a variety of novel 4(5)-(2-aminoethyl)imidazolines and their I 1, I2, α2-adrenoceptors affinities are reported.
Identification of 2-amino-5-(thioaryl)thiazoles as inhibitors of nerve growth factor receptor TrkA
Kim, Soong-Hoon,Tokarski, John S.,Leavitt, Kenneth J.,Fink, Brian E.,Salvati, Mark E.,Moquin, Robert,Obermeier, Mary T.,Trainor, George L.,Vite, Gregory G.,Stadnick, Linda K.,Lippy, Jonathan S.,You, Dan,Lorenzi, Matthew V.,Chen, Ping
, p. 634 - 639 (2008/09/18)
2-Amino-5-(thioaryl)thiazoles are potent inhibitors of TrkA (e.g., 20h, TrkA IC50 = 0.6 nM) that show anti-proliferative effect in cellular assays. A proposed inhibitor binding mode to TrkA active site is consistent with key SAR observations.
A new orally bioavailable dual adenosine A2B/A3 receptor antagonist with therapeutic potential
Press, Neil J.,Taylor, Roger J.,Fullerton, Joseph D.,Tranter, Pamela,McCarthy, Clive,Keller, Thomas H.,Brown, Lyndon,Cheung, Robert,Christie, Julie,Haberthuer, Sandra,Hatto, Julia D.I.,Keenan, Mark,Mercer, Mark K.,Press, Nicola E.,Sahri, Helene,Tuffnell, Andrew R.,Tweed, Morris,Fozard, John R.
, p. 3081 - 3085 (2007/10/03)
The synthesis and SAR of 5-heterocycle-substituted aminothiazole adenosine receptor antagonists is described. Several compounds show high affinity and selectivity for the A2B and A3 receptors. One compound (5f) shows good ADME properties in the rat and as such may be an important new compound in testing the current hypotheses proposing a therapeutic role for a dual A2B/A3 antagonist in allergic diseases.
Aminothaizoles and their use as adenosine receptor antagonists
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, (2008/06/13)
Compounds of formula (I) in free or salt form, where A is a C6-C15 monovalent aromatic group. R1 is hydrogen, phenyl optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, C1-C8-alkyl, C1-C8-haloalkyl, C1-C8-alkoxy, C1-C
Synthesis of some new 5-(2-substituted-1,3-thiazol-5-yl)-2-hydroxy benzamides and their 2-alkoxy derivatives as possible antifungal agents
Narayana,Vijaya Raj,Ashalatha,Kumari, N. Suchetha,Sarojini
, p. 867 - 872 (2007/10/03)
The 2-hydroxy-5-(1,3-thiazol-5-yl) benzamide (4a), 5-(2-amino-1, 3-thiazol-5-yl)-2-hydroxy benzamide (4b), 2-hydroxy-5-(2-alkyl-1,3-Thiazol-5-yl) benzamide (4c and 4d), 5-{2-[(N-substituted aryl)amino]-1,3-thiazol-5-yl}2- hydroxy benzamides (6a-j) were prepared by reacting 5-(bromoacetyl) salicylamide (2) with thiourea, thioformamide, thioalkylamide (3c-d) and substituted thioureas (5a-j) in absolute ethanol. These compounds were converted to 5-(2-substituted-1,3-thiazol-5-yl)-2-alkoxybenzamides and 5-(2-N-(substituted aryl)-1,3-thiazol-5-yl)-2-alkoxy benzamides (8a-g) by reacting with n-alkylbromides (7a-b) in presence of a base. The newly synthesized compounds were characterized by IR, 1H-NMR and mass spectral data. Compounds were also screened for their antifungal activity.
