Discovery Process and Pharmacological Characterization of 2-(S)-(4-Fluoro-2-methylphenyl)piperazine-1-carboxylic Acid [1-(R)-(3,5-Bis-trifluoromethylphenyl)ethyl]methylamide (Vestipitant) as a Potent, Selective, and Orally Active NK₁ Receptor Antagonist

Abstract

In an effort to discover novel druglike NK(1) receptor antagonists a new series of suitably substituted C-phenylpiperazine derivatives was identified by an appropriate chemical exploration of related N-phenylpiperazine analogues, with the specific aim to maximize their in vitro affinity and optimize in parallel their pharmacokinetic profile. Among the compounds synthesized, 2-(S)-(4-fluoro-2-methylphenyl)piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethylphenyl)ethyl]methylamide (vestipitant) was identified as one of the most in vitro potent and selective NK(1) receptor antagonists ever discovered, showing appropriate pharmacokinetic properties and in vivo activity. On the basis of its preclinical profile, this compound was selected as a drug candidate.

Application of LC–NMR to the identification of bulk drug impurities in NK1 antagonist GW597599 (vestipitant)

“…The 1D 1 H LC-NMR spectrum obtained for the first eluting compound was consistent with the 1 H NMR data for pure drug substance (1). This spectrum established also the chemical shifts of (1) in the eluent solvent system (acetonitrile/deuterium oxide, with addition of 0.1% trifluoroacetic acid (TFA)), allowing a comparative analysis with unknown compounds present in the mixture (Fig.…”

“…Also in this case, the NMR spectrum was quite similar to that of the parent compound, with the extra singlet in the aliphatic region The last impurity showed similarities with the first one. Here, the 1D 1 H LC-NMR spectrum presented a doubling of the resonances arising for bis(trifluoromethyl)phenyl-N-methylethanamine moiety in a 1 : 1 ratio by integration with respect to signals common to (1), suggesting again that the spectrum represented a single compound. These data provided the first indication that this impurity was closely related to (1), and the structure (6) A chemical rationale for all the suggested impurity structures was found, and the potential pathway for the formation of all of them in the synthetic process is shown in Fig.…”

“…The 1D 1 H LC-NMR spectrum of (2) retained similar features to those of (1), but a doubling of resonances arising for the aryl-piperidine moiety was immediately apparent. The extra resonances were determined to be present in a 1 : 1 ratio by integration with those signals common to (1), suggesting that the spectrum represented a single compound. These data provided the first indication that this impurity was closely related to (1) quite common loss of this series of impurities, and m/z 492 due to the loss of 211 u, which corresponds to the carbolyl-aryl-piperazine moiety.…”

“…GW597599 (vestipitant) (1) is a novel NK-1 antagonist currently under development for the treatment of central nervous system disorders and to relieve also CINV symptoms. [1] The synthetic scale-up in the development phase involves the full understanding of the chemical process for pursuing synthetic route robustness and drug substance chemical developability. [2 -4] In this context, the structure elucidation of impurities is a key activity that drives specific synthetic route optimisation processes and addresses potential toxicological issues, at the same time complying with regulatory guidelines.…”

Intriguing possibilities and beneficial aspects of transporter-conscious drug design

“…Representative brain-penetrant compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) [56][57][58][59][60][61][62][63][64][65][66][67][68][69] are shown in Figure 16 with the exception of nucleic acid mimics. Although these Ncontaining groups were not transporter-consciously incorporated into the molecule of designed compounds in order to control ADMET, they, especially N-alkyl groups, might eventually act as transporter recognition unit from the result of their BBB permeability.…”