1065113-62-3Relevant academic research and scientific papers
Multiparameter optimization in CNS drug discovery: Design of pyrimido[4,5-d]azepines as potent 5-hydroxytryptamine 2C (5-HT2C) receptor agonists with exquisite functional selectivity over 5-HT2A and 5-HT2B receptors
Storer, R. Ian,Brennan, Paul E.,Brown, Alan D.,Bungay, Peter J.,Conlon, Kelly M.,Corbett, Matthew S.,Depianta, Robert P.,Fish, Paul V.,Heifetz, Alexander,Ho, Danny K. H.,Jessiman, Alan S.,McMurray, Gordon,De Oliveira, Cesar Augusto F.,Roberts, Lee R.,Root, James A.,Shanmugasundaram, Veerabahu,Shapiro, Michael J.,Skerten, Melanie,Westbrook, Dominique,Wheeler, Simon,Whitlock, Gavin A.,Wright, John
supporting information, p. 5258 - 5269 (2014/07/08)
A series of 4-substituted pyrimido[4,5-d]azepines that are potent, selective 5-HT2C receptor partial agonists is described. A rational medicinal chemistry design strategy to deliver CNS penetration coupled with SAR-based optimization of selectivity and agonist potency provided compounds with the desired balance of preclinical properties. Lead compounds 17 (PF-4479745) and 18 (PF-4522654) displayed robust pharmacology in a preclinical canine model of stress urinary incontinence (SUI) and no measurable functional agonism at the key selectivity targets 5-HT2A and 5-HT2B in relevant tissue-based assay systems. Utilizing recent advances in the structural biology of GPCRs, homology modeling has been carried out to rationalize binding and agonist efficacy of these compounds.
Discovery of a novel azepine series of potent and selective 5-HT2C agonists as potential treatments for urinary incontinence
Brennan, Paul E.,Whitlock, Gavin A.,Ho, Danny K.H.,Conlon, Kelly,McMurray, Gordon
scheme or table, p. 4999 - 5003 (2010/03/31)
A range of heterocycle fused azepines were synthesized in order to find a CNS penetrant, selective 5-HT2C agonist for the treatment of incontinence. The pyridazo-azepines such as compound 11 were shown to be potent 5-HT2C agonists and have potential for CNS penetration and good in vitro ADME properties but lacked selectivity against 5-HT2B. Fusing a further heterocycle gave the selective triazolopyrimido-azepines. An example of this series, compound 36, was shown to be potent, selective, metabolically stable in vitro and efficacious in an in vivo model of stress urinary incontinence.
PYRIMIDO [4, 5-D] AZEPINE DERIVATIVES AS 5-HT2C AGONISTS
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Page/Page column 154-155, (2008/12/04)
The present invention relates to compounds of formula (I): wherein R1, R2, R3a,R3b, R3c, R3d and R100 are as defined in the specification. These compounds act as 5-HT2C agonists.
