Tetrahydroisoquinoline scaffold

In search for potent and systemically available inhibitors of the matrix metalloproteinase MMP-8 (Matter et al. 1999 Matter et al. 2002) following oral administration, a local ADME model was derived to support lead optimization. For an internal series of inhibitors on the tetrahydroisoquinoline scaffold, hydroxamic acids for zinc ion binding in 3-position are essential for MMP affinity in first generation inhibitors. However, those compounds are characterized by insufficient pharmacokinetic properties and low systemic exposure following oral administration. Driven by X-ray and 3D-QSAR studies (CoMFA), alternative Zn2+ binding groups like carboxylates were... 

Recently, Singh and co-workers reported an unprecedented Cu(I)/pybox-diPh-catalyzed highly enantioselective cascade alkynylation-lactamization reaction of readily available o-formyl methyl benzoates, aromatic amines, and terminal alkynes (Scheme 41) [66]. This protocol provides a straightforward and efficient approach to a wide range of enantiomerically enriched isoindolinones in good yield with an exceptionally high level of enantioselectivity. The methodology was further extended to the synthesis of synthetically important tetrahydroisoquinoline scaffolds in a two-step sequence with remarkable selectivity. 

Phenyl tetrahydroisoquinoline scaffold was selected as it was proven to be a convenient peripheral site binder [27]. There is a growing interest in developing multitarget-directed drugs and particularly new potent dual-binding site, AChE inhibitors are able to exert a dual action [33] (inhibition of cholinesterase activity and inhibition of AChE-mediated Ap deposition) [34]. The results of the m-AChE-directed syntheses of heterodimeric huprine-based inhibitors are summarized vide Table 2.1). 

A series of diamine amides based on the phenoxypropyl amine scaffold was reported. Amide 26 displayed an hH3 Ki of 1 nM and was selective versus other histamine receptors [73]. The chirality was removed via cyclic diamines to produce tetrahydroisoquinolines, tetrahydroquinolines, benzazepines and indolines [74]. The benzazepine 27 displayed picomolar hH3 binding affinity. Pharmacokinetic issues were also identified with this diamine series, with i.v. half-lives of 10-12 h in the rat. A strategy to remove the diamine skeleton and prepare new H3... 

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