213767-19-2Relevant articles and documents
Discovery of Tetrahydropyrazolopyridine as Sphingosine 1-Phosphate Receptor 3 (S1P3)-Sparing S1P1 Agonists Active at Low Oral Doses
Demont, Emmanuel H.,Bailey, James M.,Bit, Rino A.,Brown, Jack A.,Campbell, Colin A.,Deeks, Nigel,Dowell, Simon J.,Eldred, Colin,Gaskin, Pam,Gray, James R. J.,Haynes, Andrea,Hirst, David J.,Holmes, Duncan S.,Kumar, Umesh,Morse, Mary A.,Osborne, Greg J.,Renaux, Jessica F.,Seal, Gail A. L.,Smethurst, Chris A.,Taylor, Simon,Watson, Robert,Willis, Robert,Witherington, Jason
, p. 1003 - 1020 (2016/02/23)
FTY720 is the first oral small molecule approved for the treatment of people suffering from relapsing-remitting multiple sclerosis. It is a potent agonist of the S1P1 receptor, but its lack of selectivity against the S1P3 receptor ha
Optimization of sphingosine-1-phosphate-1 receptor agonists: Effects of acidic, basic, and zwitterionic chemotypes on pharmacokinetic and pharmacodynamic profiles
Skidmore, John,Heer, Jag,Johnson, Christopher N.,Norton, David,Redshaw, Sally,Sweeting, Jennifer,Hurst, David,Cridland, Andrew,Vesey, David,Wall, Ian,Ahmed, Mahmood,Rivers, Dean,Myatt, James,Giblin, Gerard,Philpott, Karen,Kumar, Umesh,Stevens, Alexander,Bit, Rino A.,Haynes, Andrea,Taylor, Simon,Watson, Robert,Witherington, Jason,Demont, Emmanuel,Heightman, Tom D.
, p. 10424 - 10442 (2015/02/19)
The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients results from the action of its phosphate metabolite on sphingosine-1-phosphate S1P1 receptors, while a variety of side effects have been ascribed to its S1P3 receptor activity. Although S1P and phospho-fingolimod share the same structural elements of a zwitterionic headgroup and lipophilic tail, a variety of chemotypes have been found to show S1P1 receptor agonism. Here we describe a study of the tolerance of the S1P1 and S1P3 receptors toward bicyclic heterocycles of systematically varied shape and connectivity incorporating acidic, basic, or zwitterionic headgroups. We compare their physicochemical properties, their performance in in vitro and in vivo pharmacokinetic models, and their efficacy in peripheral lymphocyte lowering. The campaign resulted in the identification of several potent S1P1 receptor agonists with good selectivity vs S1P3 receptors, efficacy at 1 mg/kg oral doses, and developability properties suitable for progression into preclinical development.
OXADIAZOLE SUBSTITUTED INDAZOLE DERIVATIVES FOR USE AS SPHINGOSINE 1-PHOSPHATE 1 (S1P1) RECEPTOR AGONISTS
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, (2012/11/13)
Oxadiazole substituted indazole derivatives of formula (I) or pharmaceutical salts thereof having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their uses in the treatment of various disorders mediated by S1P1 receptors are disclosed.
Identification of benzoxazole analogs as novel, S1P3 sparing S1P1 agonists
Deng, Guanghui,Meng, Qinghua,Liu, Qian,Xu, Xuesong,Xu, Qiongfeng,Ren, Feng,Guo, Taylor B.,Lu, Hongtao,Xiang, Jia-Ning,Elliott, John D.,Lin, Xichen
scheme or table, p. 3973 - 3977 (2012/07/03)
A novel series of benzoxazole-derived S1P1 agonists were designed based on scaffold hopping molecular design strategy combined with computational approaches. Extensive SAR studies led to the discovery of compound 17d as a selective S1P1 agonist (over S1P3) with high CNS penetration and favorable DMPK properties. 17d also demonstrated in vivo pharmacological efficacy to reduce blood lymphocyte in mice after oral administration.
OXADIAZOLE SUBSTITUTED INDAZOLE DERIVATIVES FOR USE AS SPHINGOSINE 1-PHOSPHATE 1 (S1P1) RECEPTOR AGONISTS
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, (2011/07/07)
Oxadiazole substituted indazole derivatives of formula (I) or pharmaceutical salts thereof having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their uses in the treatment of various disorders mediated by S1P1 receptor are disclosed.
Discovery of a selective S1P1 receptor agonist efficacious at low oral dose and devoid of effects on heart rate
Demont, Emmanuel H.,Andrews, Benjamin I.,Bit, Rino A.,Campbell, Colin A.,Cooke, Jason W. B.,Deeks, Nigel,Desai, Sapna,Dowell, Simon J.,Gaskin, Pam,Gray, James R. J.,Haynes, Andrea,Holmes, Duncan S.,Kumar, Umesh,Morse, Mary A.,Osborne, Greg J.,Panchal, Terry,Patel, Bela,Perboni, Alcide,Taylor, Simon,Watson, Robert,Witherington, Jason,Willis, Robert
supporting information; experimental part, p. 444 - 449 (2011/08/08)
Gilenya (fingolimod, FTY720) was recently approved by the U.S. FDA for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). It is a potent agonist of four of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors (S1P1 and S1P3-5). It has been postulated that fingolimod's efficacy is due to S1P1 agonism, while its cardiovascular side effects (transient bradycardia and hypertension) are due to S1P3 agonism. We have discovered a series of selective S1P 1 agonists, which includes 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy] phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl] propanoate, 20, a potent, S1P3-sparing, orally active S1P1 agonist. Compound 20 is as efficacious as fingolimod in a collagen-induced arthritis model and shows excellent pharmacokinetic properties preclinically. Importantly, the selectivity of 20 against S1P3 is responsible for an absence of cardiovascular signal in telemetered rats, even at high dose levels.
Discovery and development of an efficient, scalable, and robust route to the novel CENP-E inhibitor GSK923295A
Bellingham, Richard,Buswell, A. Mark,Choudary, Bernie M.,Gordon, Andrew H.,Moore, Steve O.,Peterson, Matthew,Sasse, Mike,Shamji, Amin,Urquhart, Michael W. J.
, p. 1254 - 1263 (2011/04/24)
The discovery and development of an efficient manufacturing route to the CENP-E inhibitor 3-chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)- 1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl} -4-[(1-methylethyl)oxy]benzamide (GSK923295A) is described. The existing route to GSK923295A was expensive, nonrobust, used nonideal reagents, and consistently struggled to deliver the API needed for clinical studies. The new synthesis commences from the readily available l-phenylalaninol, which is smoothly converted through to GSK923295A using key Friedel-Crafts acylation as well as selective acylation chemistries. Downstream chemistry to GSK923295A is both high yielding and robust, and the resulting process has been demonstrated first on the kilo scale and subsequently in the pilot plant where 55 kg was successfully prepared. The resulting process is simple, uses cheaper raw materials, is greener in that it avoids using aluminum, tin, and bromination chemistries, and obviates the need for chromatographic purification. Also discussed are the route derived impurities, how they were unambiguously prepared to confirm structure and processing amendments to control their formation, and enhancements to the new process to facilitate future processing.
OXADIAZOLE DERIVATIVES ACTIVE ON SPHINGOSINE-1-PHOSPHATE (S1P)
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Page/Page column 24-25, (2009/07/25)
The present application discloses oxadiazote based compounds of Formula (I) active on sphingosine-1-phosphate (S1P) in particular useful to treat lupus erythematosus. A is phenyl or a 5 or 6-membered heleroaryl ring; B is selected from one of the followin
