- Design, synthesis, and evaluation of conformationally restricted acetanilides as potent and selective β3 adrenergic receptor agonists for the treatment of overactive bladder
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A series of conformationally restricted acetanilides were synthesized and evaluated as β3-adrenergic receptor agonists (β3-AR) for the treatment of overactive bladder (OAB). Optimization studies identified a five-membered ring as the preferred conformational lock of the acetanilide. Further optimization of both the aromatic and thiazole regions led to compounds such as 19 and 29, which have a good balance of potency and selectivity. These compounds have significantly reduced intrinsic clearance compared to our initial series of pyridylethanolamine β3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent β3-AR mediated responses in a rat bladder hyperactivity model.
- Moyes, Christopher R.,Berger, Richard,Goble, Stephen D.,Harper, Bart,Shen, Dong-Ming,Wang, Liping,Bansal, Alka,Brown, Patricia N.,Chen, Airu S.,Dingley, Karen H.,Di Salvo, Jerry,Fitzmaurice, Aileen,Gichuru, Loise N.,Hurley, Amanda L.,Jochnowitz, Nina,Miller, Randall R.,Mistry, Shruty,Nagabukuro, Hiroshi,Salituro, Gino M.,Sanfiz, Anthony,Stevenson, Andra S.,Villa, Katherine,Zamlynny, Beata,Struthers, Mary,Weber, Ann E.,Edmondson, Scott D.
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supporting information
p. 1437 - 1453
(2014/03/21)
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- MULTICYCLIC COMPOUNDS AND METHODS OF USE THEREOF
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Provided herein are multicyclic compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. The compounds provided herein are useful for the treatment, prevention, and/or management of various neurological disorders, including but not limited to, psychosis and schizophrenia.
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Page/Page column 102
(2011/06/25)
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- COMBINATION THERAPY USING A BETA 3 ADRENERGIC RECEPTOR AGONIST AND AN ANTIMUSCARINIC AGENT
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Described herein is an improved method of treating overactive bladder, wherein the method comprises administering to a patient in need thereof a beta 3 adrenergic receptor agonist, an antimuscarinic agent, and an optional selective M2 antagonist. Such combination therapy provides improved efficacy and/or reduced side effects.
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Page/Page column 29
(2011/04/26)
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- HYDROXYMETHYL PYRROLIDINES AS BETA 3 ADRENERGIC RECEPTOR AGONISTS
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The present invention provides compounds of Formula (I), pharmaceutical compositions thereof, and method of using the same in the treatment or prevention of diseases mediated by the activation of β3-adrenoceptor.
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Page/Page column 30
(2009/10/17)
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- FUSED HETEROCYCLIC DERIVATIVES AS PPAR MODULATORS
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The present invention is directed to compounds represented by the following structural formula, Formula I: wherein (a) X is selected from the group consisting of a single bond, O, S. S(O)2 and N; (b) U is an aliphatic linker; (c) Y is selected from the group consisting of C, O, S, NH and a single bond; (d) E is C(R3) (R4)A or A and wherein (i) A is selected from the group consisting of carboxyl, tetrazole, C1-C6 alkylnitrile, carboxamidek, sulfonamide and acylsulfonamide; (e) B is selected from the group consisting of S, O, C, and N; (f) Z is selected from the group consisting of N and C; with the proviso that when B is C then Z is N.
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- A convenient synthesis of 4-aminomethyl-4,5,6,7-tetrahydro-1,3-benzothiazole arginine side-chain mimetics
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A convenient synthesis of novel 4-aminomethyl-4,5,6,7-tetrahydro-1,3-benzothiazole arginine side-chain mimetics designed for incorporation into thrombin inhibitors is reported.
- Marinko, Petra,Kastelic, Jo?e,Krbav?i?, Ale?,Kikelj, Danijel
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p. 8911 - 8913
(2007/10/03)
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- Condensed Tetrahydrobenzothiazoles: Part I- Synthesis of 2-Substituted Anilino-4,5,6,7-tetrahydrobenzothiazoles and Their 4-Carbethoxy Derivatives
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Condensation of the appropriate 2-halocyclohexanone (I) with arylthiourea (II) affords a number of 2-substituted anilino-4,5,6,7-tetrahydrobenzothiazoles (IIIa) and their 4-carbethoxy esters (IIIb).Influence of steric factors and nucleophilicity of the reactants on the course of this reaction are discussed.
- Balse, Mukta N.,Mahajanshetti, C. S.
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p. 256 - 259
(2007/10/02)
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