957121-52-7Relevant academic research and scientific papers
Identification of Morpholino-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-ones as Nonsteroidal Mineralocorticoid Antagonists
Piotrowski, David W.,Futatsugi, Kentaro,Casimiro-Garcia, Agustin,Wei, Liuqing,Sammons, Matthew F.,Herr, Michael,Jiao, Wenhua,Lavergne, Sophie Y.,Coffey, Steven B.,Wright, Stephen W.,Song, Kun,Loria, Paula M.,Banker, Mary Ellen,Petersen, Donna N.,Bauman, Jonathan
, p. 1086 - 1097 (2018/02/17)
A novel series of morpholine-based nonsteroidal mineralocorticoid receptor antagonists is reported. Starting from a pyrrolidine HTS hit 9 that possessed modest potency but excellect selectivity versus related nuclear hormone receptors, a series of libraries led to identification of morpholine lead 10. After further optimization, cis disubstituted morpholine 22 was discovered, which showed a 45-fold boost in binding affinity and corresponding functional potency compared to 13. While 22 had high clearance in rat, it provided sufficient exposure at high doses to favorably assess in vivo efficacy (increased urinary Na+/K+ ratio) and safety. In contrast to rat, the dog and human MetID and PK profiles of 22 were adequate, suggesting that it could be suitable as a potential clinical asset.
SUBSTITUTED MORPHOLINE DERIVATIVES AS ROR GAMMA MODULATORS
-
Page/Page column 30-31, (2018/07/29)
The present disclosure is directed to compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein ring A, R1, R2, R3, X1, X2, m and n are as defined herein, which are active as modulators of retinoid-related orphan receptor gamma t (RORyt). These compounds prevent, inhibit, or suppress the action of RORyt and are therefore useful in the treatment of RORyt mediated diseases, disorders, syndromes or conditions such as, e.g., pain, inflammation, COPD, asthma, rheumatoid arthritis, colitis, multiple sclerosis, psoriasis, neurodegenerative diseases and cancer. (I)
Synthesis of a cis 2,5-disubstituted morpholine by de-epimerization: Application to the multigram scale synthesis of a mineralocorticoid antagonist
Sammons, Matthew,Jennings, Sandra M.,Herr, Michael,Hulford, Catherine A.,Wei, Liuqing,Hallissey, James F.,Kiser, E. Jason,Wright, Stephen W.,Piotrowski, David W.
, p. 934 - 939 (2013/07/26)
A convergent route to multigram quantities of a mineralocorticoid antagonist 3 is described. Starting from (R)-phenylglycinol, the synthesis of cis 2,5-morpholine 2 is accomplished utilizing a de-epimerization to install the second stereogenic center. The multigram synthesis of 3 was completed through a sequence of an SNAr reaction, Dakin oxidation, alkylation, and cyclization to provide a crystalline solid.
MORPHOLINE COMPOUNDS
-
Page/Page column 18, (2011/11/30)
Mineralocorticoid receptor antagonists (MRa), pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat, for example, diabetic nephropathy and hypertension in mammals, including humans.
Substituted monocyclic CGRP receptor antagonists
-
Page/Page column 42, (2008/06/13)
Compounds of formula I: (wherein variables A1, A2, A3, A4, m, n, J, Q, R4, Ea, Eb, Ec, R6, R7, Re, Rf, RPG and Y are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
