piperidines and isoquinoline

Rho kinase is an important target implicated in a variety of cardiovascular diseases. Herein, we report the optimisation of the fragment derived ATP-competitive ROCK inhibitors 1 and 2 into lead compound 14A. The initial goal of improving ROCK-I potency relative to 1, whilst maintaining a good PK profile, was achieved through removal of the aminoisoquinoline basic centre. Lead 14A was equipotent against both ROCK-I and ROCK-II, showed good in vivo efficacy in the spontaneous hypertensive rat model, and was further optimised to demonstrate the scope for improving selectivity over PKA versus hydroxy Fasudil 3.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Amines; Animals; Disease Models, Animal; Hypertension; Isoquinolines; Models, Chemical; Models, Molecular; Piperidines; Protein Kinase Inhibitors; Quinolones; Rats; rho-Associated Kinases; Structure-Activity Relationship

Several caspases have been implicated in the pathogenesis of Huntington's disease (HD); however, existing caspase inhibitors lack the selectivity required to investigate the specific involvement of individual caspases in the neuronal cell death associated with HD. In order to explore the potential role played by caspase-2, the potent but non-selective canonical Ac-VDVAD-CHO caspase-2 inhibitor 1 was rationally modified at the P(2) residue in an attempt to decrease its activity against caspase-3. With the aid of structural information on the caspase-2, and -3 active sites and molecular modeling, a 3-(S)-substituted-l-proline along with four additional scaffold variants were selected as P(2) elements for their predicted ability to clash sterically with a residue of the caspase-3 S(2) pocket. These elements were then incorporated by solid-phase synthesis into pentapeptide aldehydes 33a-v. Proline-based compound 33h bearing a bulky 3-(S)-substituent displayed advantageous characteristics in biochemical and cellular assays with 20- to 60-fold increased selectivity for caspase-2 and ∼200-fold decreased caspase-3 potency compared to the reference inhibitor 1. Further optimization of this prototype compound may lead to the discovery of valuable pharmacological tools for the study of caspase-2 mediated cell death, particularly as it relates to HD.

Topics: Binding Sites; Caspase 2; Caspase 3; Caspase Inhibitors; Catalytic Domain; Cell Line; Cysteine Proteinase Inhibitors; Drug Design; Humans; Isoquinolines; Molecular Dynamics Simulation; Piperidines; Proline; Substrate Specificity

Crystal structures of nine non-peptide tachykinin NK1 antagonists have been analysed for the intermolecular interactions of their pharmacophoric groups with neighbouring molecules in the crystals. Experimental data on interaction geometries of these antagonists with their environment can be of help in understanding the mechanism of binding to the human NK1 receptor. Several interaction geometries have been identified that are consistent with both structure-activity relationships and reported receptor interactions for the compounds analysed. In addition, an interaction site for the side-chain of Gln-165 in the human NK1 receptor that is probably involved in donating a hydrogen bond to the benzylamino nitrogen or benzylether oxygen of the quinuclidine and piperidine antagonists is explicitly postulated. Also, a superposition based on pharmacophoric elements in the crystal structure conformations of two prototypic NK1 antagonists, CP-96,345 (1) and CP-99,994 (4), suggests how both compounds might interact with the human NK1 receptor in a similar manner.

Topics: Binding Sites; Crystallography, X-Ray; Humans; Hydrogen Bonding; Isoquinolines; Ligands; Magnetic Resonance Spectroscopy; Models, Molecular; Neurokinin-1 Receptor Antagonists; Piperidines; Protein Conformation; Pyridines; Quinuclidines; Software; Tryptophan