A novel series of pyrido [4,3-e][1,2,4]triazolo- [4,3-a]pyrazines is reported as potent PDE2/PDE10 inhibitors with drug-like properties. Selectivity for PDE2 was obtained by introducing a linear, lipophilic moiety on the meta-position of the phenyl ring pending from the triazole. The SAR and protein flexibility were explored with free energy perturbation calculations. Rat pharmacokinetic data and in vivo receptor occupancy data are given for two representative compounds 6 and 12.

Two benzazaborinine analogues of propranolol were synthesized and extensively profiled in vitro and in vivo. These analogues showed potency and physicochemical and in vitro ADME-tox profiles comparable to propranolol. In addition, both benzazaborinine analogues showed excellent bioavailability and brain penetration following subcutaneous administration in a pharmacokinetic study in rats. These studies unveil the potential of aromatic azaborinines as bioisosteric replacements of naphthalene in drug discovery programs.

N-Acyl-4-acyloxy-beta-lactams are converted into 1,3-oxazin-6-ones under basic conditions. This transformation is believed to proceed via N-acylazetones, which rearrange to the final products by a sequence of two electrocyclic processes. The calculated (RHF and B3LYP) transition structures of both concerted reactions are shown to present characteristic pseudopericyclic orbital topologies.

Intramolecular ketenimine ± imine [22] cycloadditions leading to 1,2-dihydroazeto[2,1-b]quinazolines occur in a notably stereocontrolled manner along the newly formed C ± C single bond when prochiral ketenimine and imine fragments are combined. Computational studies support stepwise mechanisms for these reactions. In sharp contrast with other well-known [22] cycloadditions, the first step of the reaction determines its stereochemical outcome, thereby surpassing the low stereocontrol induced by torquoelectronic effects.

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