The discovery of new highly potent and selective dopamine D3 receptor antagonists has recently permitted characterization of the role of the dopamine D3 receptor in a wide range of preclinical animal models. A novel series of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines demonstrating a high level of D3 affinity and selectivity with an excellent pharmacokinetic profile is reported here. In particular, the pyrazolyl derivative 35 showed good oral bioavailability and brain penetration associated with high potency and selectivity in vitro. In vivo characterization of 35 confirmed that this compound blocks the expression of nicotine- and cocaine-conditioned place preference in the rat, prevents nicotine-triggered reinstatement of nicotine-seeking behavior in the rat, reduces oral operant alcohol self-administration in the mouse, increases extracellular levels of acetylcholine in the rat medial prefrontal cortex, and potentiates the amplitude of the relative cerebral blood volume response to d-amphetamine in a regionally specific manner in the rat brain.
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.
As a result of their wide acceptance and conceptual simplicity, drug-like concepts are having a major influence on the drug discovery process, particularly in the selection of the 'optimal' absorption, distribution, metabolism, excretion and toxicity and physicochemical parameters space. While they have an undisputable value when assessing the potential of lead series or in evaluating inherent risk of a portfolio of drug candidates, they result much less useful in weighing up compounds for the selection of the best potential clinical candidate. We introduce the concept of drug efficiency as a new tool both to guide the drug discovery program teams during the lead optimization phase and to better assess the developability potential of a drug candidate.
(2S)-2-Methoxycyclohexanone
[(2S)-6], reacts with the 4-acetoxyazetidinone
3a in the presence of
SnCl4 and a tertiary amine base (such as
N,N-diisopropylethylamine) to give the
ketoazetidinone
5 (a key intermediate in the synthesis of the broad-spectrum
antibiotic sanfetrinem 2a) with high
yield and diastereoselectivity. Low-temperature NMR studies of the
reaction indicated the formation
of a 1:1 chelate complex 11 between SnCl4 and
(2S)-6 which, on addition of the base is
transformed
into the highly reactive chelated tin enolate 12. The
formation of compound 11 has been confirmed
by single-crystal X-ray analysis. The high diastereoselectivity
observed is believed to derive from
an open transition state where the chelated SnCl4 amplifies
the stereochemical influence of the
methoxy group. This reaction offers considerable advantages over
all existing syntheses of the
ketoazetidinone 5 and is currently under evaluation for
inclusion in the industrial synthesis of
sanfetrinem.
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