1065110-62-4Relevant 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.
Pyrimido[4,5-d]azepines as potent and selective 5-HT2C receptor agonists: Design, synthesis, and evaluation of PF-3246799 as a treatment for urinary incontinence
Andrews, Mark D.,Fish, Paul V.,Blagg, Julian,Brabham, Tiffini K.,Brennan, Paul E.,Bridgeland, Alison,Brown, Alan D.,Bungay, Peter J.,Conlon, Kelly M.,Edmunds, Nicholas J.,Af Forselles, Kerry,Gibbons, Colleen P.,Green, Martin P.,Hanton, Giles,Holbrook, Mark,Jessiman, Alan S.,McIntosh, Karin,McMurray, Gordon,Nichols, Carly L.,Root, James A.,Storer, R. Ian,Sutton, Michael R.,Ward, Robin V.,Westbrook, Dominique,Whitlock, Gavin A.
, p. 2715 - 2720 (2011/06/22)
New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT2C receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT2A or 5-HT2B receptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection.
PYRIMIDO [4, 5-D] AZEPINE DERIVATIVES AS 5-HT2C AGONISTS
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, (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.
