An aprepitant (compound 1) is now the sole marketed NK1R drug. Merck's chemists designed novel hydroisoindoline-based NK1R antagonists by merging an aprepitant with a vinylogous amide 2. It was very impressed that five chiral stereocenters were manipulated by Diels-Alder reaction and the ether formation with the trichloroacetimidate derivative.
NMR spectroscopy, X-ray crystallography, and molecular modeling studies indicate that N,N-disubstituted-1,4-diazepane orexin receptor antagonists exist in an unexpected low-energy conformation that is characterized by an intramolecular π-stacking interaction and a twist-boat ring conformation. It is interesting that an exo-cyclic amide bond might trigger a change in ring conformation from chair to boat. Synthesis and evaluation of a macrocycle that enforces a similar conformation suggest that this geometry mimics the bioactive conformation. The key synthetic steps of this fascinating macrocyclic structure are a copper-catalyzed C-N cross-coupling, an allylation by Stille coupling, a Negishi coupling with pentenylzinc bromide, and a RCM with Zhan-1B catalyst.
A mechanistic hypothesis for the acetylation of cyclooxygenase (COX) by aspirin is proposed on the basis of a QM/MM study. This mechanism is consistent with previous experimental findings by other investigators. Ser 530 appears to be acetylated under intramolecular general base catalysis provided by the carboxylate moiety of aspirin, while Tyr 385 plays a crucial role in orienting and polarizing the acetyl group.
The initial hit comound 1 without a transition-state isoster has a week potency (IC50 = 217 maicro M), but its compact size represented an alluring ligand efficiency value of 0.3. Lead optimizatin gave the compound 7 (IC50 = 3.2 micro M), which showed unique binding mode to the enzyme: 1) Interaction directly with the catalytic dyad through a bidentate interaction; 2)The methoxy phenyl portion was observed to be involved in an extended face-to-point-to face pai-stack with Phe-108 and Phe-109; 3) The inhibitor bound in a 'flap-open' enzyme conformation.
Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin inhibitors. Oral adminstration of lead compound 21l, with MW of 508 and IC50 of 0.47 nM, caused a sustained reduction in mean arterial blood pressure in a double transgenic rat model of hypertension.
Drug design was focused on metabolically stable potent NPY5 R antagonists without hERG inhibition. It is interesting that methyl insertion of 5 position of imidazoline improved potency and reduced hERG inhibition. Reduced lipophilicity strategy also succeeded in reduction of hERG inhibition. In addition, it should be noted that an excellent correlation was observed between the log D values and CSF-to-brain ratios. It is an useful knowledge that this correlation is generally valid for a series of structurally close analogues that have similar pKa values, probably because basicity is an important parameter that significantly influences brain tissue binding.