Discovery of 4-Phenylpiperidine-2-Carboxamide Analogues as Serotonin 5-HT2CReceptor-Positive Allosteric Modulators with Enhanced Drug-like Properties
Targeting the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) allosteric site to potentiate endogenous 5-HT tone may provide novel therapeutics to alleviate the impact of costly, chronic diseases such as obesity and substance use disorders. Expanding upon our recently described 5-HT2CR-positive allosteric modulators (PAMs) based on the 4-alkylpiperidine-2-carboxamide scaffold, we optimized the undecyl moiety at the 4-position with variations of cyclohexyl- or phenyl-containing fragments to reduce rotatable bonds and lipophilicity. Compound 12 (CTW0415) was discovered as a 5-HT2CR PAM with improved pharmacokinetics and reduced off-target interactions relative to our previous series of molecules. The in vivo efficacy of compound 12 to potentiate the effects of a selective 5-HT2CR agonist was established in a drug discrimination assay. Thus, 12 is reported as a 5-HT2CR PAM with characteristics suitable for in vivo pharmacological studies to further probe the biological and behavioral mechanisms of allosteric modulation of a receptor important in several chronic diseases.
Wold, Eric A.,Garcia, Erik J.,Wild, Christopher T.,Miszkiel, Joanna M.,Soto, Claudia A.,Chen, Jianping,Pazdrak, Konrad,Fox, Robert G.,Anastasio, Noelle C.,Cunningham, Kathryn A.,Zhou, Jia
p. 7529 - 7544
(2020/08/21)
Allosteric modulators of 5-hydroxytryptamine 2C receptor (5-HT2CR)
The disclosure is directed to compounds identified as allosteric modulators of 5-HT 2CR, as well as pharmaceutical compositions and methods using the same. Certain embodiments also include methods of identifying and methods of synthesizing the compounds. Optimization and development of allosteric 5-HT 2CR modulators that bind sites other than the primary ligand binding site generate novel, highly selective, and potent ligands of 5-HT2CR. Such molecules can be used as small molecule probes for the nervous system and as effective therapeutics for a variety of diseases.
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(2017/01/26)
ALLOSTERIC MODULATORS OF 5-HYDROXYTRYPTAMINE 2C RECEPTOR (5-HT2CR)
[000166] Embodiments of the invention are directed to methods of identifying, methods of synthesizing, and compositions identified as allosteric modulators of 5-HT2cR.
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(2013/06/27)
Synthesis of chiral nonracemic 4-trans-substituted pipecolic acid derivatives
The syntheses and resolutions of enantiomerically enriched 4-phenyl, 4- tert-butyl, and 4-isopropyl pipecolic acids are described. Optically active diastereomers were prepared by diastereomeric salt formation with the chiral base, L-tyrosine hydrazide, to
Keenan, Terence P.,Yaeger, David,Holt, Dennis A.
p. 4331 - 4341
(2007/10/03)
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