piperidines and indacrinone

The process chemists' primary responsibility is to develop efficient and reproducible syntheses of pharmaceutically active compounds. This task is complicated when dealing with chiral molecules that often must be made as single isomers according to regulatory guidelines. The presence of any isomeric impurity in the final product, even in small amounts, is usually not acceptable. This requirement necessitates an exquisite understanding of the methods employed in the construction of chiral drugs. However, the chemistry available for this purpose is sometimes limited and often requires a significant amount of effort and creativity to be made both functional and consistent.

Topics: Animals; Carbapenems; Combinatorial Chemistry Techniques; Endothelin Receptor Antagonists; Humans; Indans; Muscarinic Antagonists; Pharmaceutical Preparations; Piperidines; Stereoisomerism; Substance P

We report on a series of hybrid compounds structurally derived from donepezil and AP2238. This study was aimed at improving the activities of the reference compounds, donepezil and AP2238, and at broadening the range of activities of new derivatives as, due to the multifactorial nature of AD, molecules that modulate the activity of a single protein target are unable to significantly modify the progression of the disease. In particular, the indanone core from donepezil was linked to the phenyl-N-methylbenzylamino moiety from AP2238, through a double bond that was kept to evaluate the role of a lower flexibility in the biological activities. Moreover, SAR studies were performed to evaluate the role of different substituents in position 5 or 6 of the indanone ring in the interaction with the PAS, introducing also alkyl chains of different lengths carrying different amines at one end. Derivatives 21 and 22 proved to be the most active within the series and their potencies against AChE were in the same order of magnitude of the reference compounds. Compounds 15, 21-22, with a 5-carbon alkyl chain bearing an amino moiety at one end, better contacting the PAS, remarkably improved the inhibition of AChE-induced Abeta aggregation with respect to the reference compounds. They also showed activity against self-aggregation of Abeta(42) peptide, the most amyloidogenic form of amyloid produced in AD brains, while the reference compounds resulted completely ineffective.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Antineoplastic Combined Chemotherapy Protocols; Benzylamines; Binding Sites; Bleomycin; Cholinesterase Inhibitors; Computer Simulation; Coumarins; Donepezil; Humans; Indans; Lomustine; Methotrexate; Peptide Fragments; Piperidines; Recombinant Proteins; Stilbenes; Structure-Activity Relationship; Tetrahydronaphthalenes

QSAR analyses have been performed on the substituted indanone and benzylpiperidine ring substructures of a set of acetylcholinesterase, AChE, inhibitors of which 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride is a potent in vitro and ex vivo inhibitor. The method of molecular decomposition-recomposition was used to define the sets of molecular substructures and corresponding in vitro inhibition databases. A QSAR involving the magnitude of the dipole moment, the highest occupied molecular orbital (HOMO) energy, and a specific pi-orbital wave function coefficient of the substituted indanone ring substructure was constructed and found to be significant. The absence of any molecular-shape or bulk term in the QSAR, coupled with some of the relatively large substituents used to construct the QSAR, suggests considerable space is available around the indanone ring during the inhibition process. A set of QSARs were constructed and evaluated for substituents on the aromatic ring of the benzylpiperidine substructure. The most significant QSAR involves a representation of molecular shape, the largest principal moment of inertia, and the HOMO of the substituted aromatic ring. It appears that upon binding the receptor "wall" is closely fit around the benzyl ring, especially near the para position. Overall, the QSAR analysis suggests inhibition potency can be better enhanced by substitution on the indanone ring, as compared to the aromatic sites of the benzylpiperidine ring. Moreover, inhibition potency can be rapidly diminished, presumably through steric interactions with the receptor surface of AChE, by substitution of moderate to large groups on the benzyl ring, particularly at the para position.

Topics: Cholinesterase Inhibitors; Indans; Models, Molecular; Piperidines; Structure-Activity Relationship

Conformational analyses and molecular-shape comparisons were carried out on an analogue series of indanone-benzylpiperidine inhibitors of acetylcholinesterase (AChE). It was possible to define an active conformation with respect to the flexible geometry of the benzylpiperidine moiety, as well as an active conformation of the indanone ring-piperidine ring substructure for analogues having a single spacer group between these rings. No active conformation could be postulated for analogues having two or three spacer units between the indanone and piperidine conformation could be postulated for analogues having two or three spacer units between the indanone and piperidine rings. Still, a receptor binding model can be constructed for all indanone and piperidine ring substructures. The postulated active conformation for 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride (1a), a potent AChE inhibitor, is close to the crystal structures of 1a with respect to the indanone-piperidine substructure, but differs from the crystal structures for the benzylpiperidine moiety. However, the crystal conformations and the postulated active conformation of the benzylpiperidine portion of the AChE inhibitor are estimated to be about equally stable. A trans-decalin analogue of 1a can adopt the postulated active conformation as shown by calculation and as seen in its crystal structure. The inactivity of this analogue is explained by the added steric size of the decalin unit and/or the time-average valence geometry behavior at the spiro junction to the indanone ring.

Topics: Cholinesterase Inhibitors; Indans; Models, Molecular; Molecular Conformation; Piperidines; X-Ray Diffraction