Inhibitor neurokinin

Neurokinin effects are terrninated by proteolysis. In vitro acetylcholinesterase (ACE) and enkephalinase can hydrolyze substance P. However, there appears to be no clear evidence that either acetylcholinesterase or ACE limit the actions of released substance P. Enkephalinase inhibitors, eg, thiorphan, can augment substance P release or action in some systems but the distribution of enkephalinase in the brain does not precisely mirror that of substance P. There appears to be a substance P-selective enzyme in brain and spinal cord. 

Neurokinin NK3 receptor antagonist and MMP Collagenase-1 inhibitor from orthogonal sets of 1600 member amide/ester library... 

In the fields of allergy and respiration, examples include 2-oxo-3-aminoazepine derivatives which act as dual neurokinin (tachykinin) NK1/NK2 receptor probes for development of options for treatment of asthsma and other airway diseases <07BMCL890> and benzo[l, 5]diazepine derivatives as new non-steroidal inhibitors of 17-P-hydroxysteroid dehydrogenase, an enzyme associated with hormone-dependent and neuronal diseases <07JEIMC29>. 

A neurokinin inhibitor whose strueture differs markedly from aprepitant (200) incorporates a substituted tetrazole ring. The synthesis of the tetrazole-containing moiety of vofopitant (241) start by acylation of substituted aniline 231 with trifluoroaeetyl ehloride to afford the amide (232). Reaction of that under Mitsonobu eonditions leads to the enol chloride (233). Treatment of 233 with sodium azide probablty starts with addition-elimination of azide ion this undergoes internal 1,3-cycloaddition to form the tetrazole ring. Catalytie hydrogenation then removes the benzyl... 

Another description of large scale analysis come from AstraZeneca in a study directed towards the synthesis of a neurokinin inhibitor of the central nervous system [100]. The synthesis inherited from the research stage already contained a Newman-Kwart rearrangement for the introduction of the sulfur atom (Scheme 40). This step was maintained in the reaction scale-up [101,102]. 

Cheung, D., Bel, E.H., Den Hartigh, J. etal. (1992). The effect of an inhaled neutral endopeptidase inhibitor, thiorphan, on airway responses to neurokinin A in normal humans in vivo. Am. Rev. Respir. Dis. 145, 1275-1280. 

Derivatives of annulated benzoindolo-l,5-naphthyridines attempting to improve memory were described (1985FRP2548667, 1987BCJ3797). These are benzo[Z>][l,5]nap-hthyridines, which are analogs of inhibitors of neurokinin NKi-receptors. Various 1,5-naphthyridine derivatives, in particular, 2-naphthyridinecarboxamide, possessing antiviral activity were also reported (1999PIAW09929318). 

Long-chain terpenes, SCH 60065 (11) and nine other related analogs, have been isolated from Acremonium sp. (Hedge et al., 1997). These compounds are neurokinin (NK) receptor inhibitors with IC50 values ranges of 2.5 -11 pM (NKi) and 6.8-16 pM (NK2). 

Hedge VR, Dai P, Chu M, Patel M, Bryant R, Terracciano J, Das PR, Puar MS. Neurokinin receptor inhibitors fermentation, isolation, physico-chemical properties, structure and biological activity. J Antibiot 50 983-991, 1997. 

A large number of reported peptidomimetic compounds possess very low aqueous solubility at physiological pH owing to the high lipophilicity inherent in these structures. Phosphorylation can yield improved biological activities for such compounds. This is at least the case for the phosphorylated neurokinin-1 receptor antagonist and the HIV protease inhibitor of Fig. 36.7 described by scientists from Merck and Upjohn, respectively. Clean phosphorylation methods are now available some of them are shown in Fig. 36.8. 

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