Evidence supports that the serotonin 2C (5-HT2C) receptor is a regulatory component of neurobehavioral processes, and aberrant signaling at this receptor may contribute to several CNS disorders such as depression, schizophrenia, impulsivity disorders and drug addiction. To augment pathologically-decreased signaling, positive allosteric modulators (PAMs) of the 5-HT2C receptor represent a favorable strategy to selectively enhance the functional response to endogenous 5-HT while preserving spacial and temporal signaling features. Therefore, to achieve a 5-HT2C receptor PAM lead compound, we introduced chemical modifications to simplify and optimize PNU-69176E, the only reported synthetic 5-HT2C receptor PAM. Our initial chemistry and SAR resulted in CYD-1-79 as a novel, selective 5-HT2C receptor PAM with improved drug-likeness. To achieve CYD-1-79, an optically pure 1,2-propanediol was introduced to the piperidine 4-carboxamide. We then continued to a second series of analogues, in which we challenged the assumption that the piperidine 2-position undecyl moiety was a privileged fragment. Excitingly, this recent series has yielded CTW0415, which retained 1,2-propanediol and introduced a phenyl to the piperidine 4-position, replacing the undecyl moiety. This chemical modification resulted in a “lead-like” 5-HT2C receptor PAM that displays markedly improved distribution, metabolism and pharmacokinetic (DMPK) properties while retaining selectivity and efficacy at the 5-HT2C receptor. In conclusion, these efforts have yielded a selective and efficacious 5-HT2C receptor PAM lead compound that exhibits promising DMPK properties and modulates 5-HT2C receptor-associated behaviors, <i>in vivo</i>, in a dose-dependent manner. CTW0415 can perform as a unique tool to elucidate neuropathological serotonergic function, and further optimization will yield promising therapeutic candidates with a potential for a first-in-class neurotherapeutic.

Discovery and synthesis of 4-phenylpiperidine-2-carboxamides as selective 5-HT2C receptor positive allosteric modulators

254th National Meeting (2017)

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