Phenoxymethyl 1,3-oxazoles and 1,2,4-oxadiazoles as potent and selective agonists of free fatty acid receptor 1 (GPR40).

A screening hit that showed a weak (EC50 = 18 μM), partial agonistic effect on GPR40 was used a prototype for expedited hit expansion effort using a set of advanced building blocks. The latter yielded several 1,3-oxazoles and 1,2,4-oxadiazoles with significantly improved potency (best EC50 = 0.058 μM).

An improved kilogram-scale preparation of atorvastatin calcium.

Background: If literature protocols are followed, conversion of an advanced ketal ester intermediate (available in kilogram quantities via a published Paal-Knorr synthesis) to cholesterol-lowering drug atorvastatin calcium is hampered by several process issues, particularly at the final stage where the hemi-calcium salt is obtained.

Results: We developed a high-yielding synthesis of atorvastatin calcium salt on 7 kg scale that affords >99.5% product purities by introducing the following key improvements: i.

Biologically active compounds based on the privileged 2-imidazoline scaffold: The world beyond adrenergic/imidazoline receptor modulators.

2-Imidazolines are well known as pharmacophores for various isoforms of adrenergic (α) and imidazoline (I) receptors. The biological activities exerted through the modulation of these targets, mostly in the central nervous system, have found utility in the development of many drug candidates - and even marketed drugs - for hypertension, diabetes and various CNS disorders. However, there is a growing evidence for the general privileged character of the 2-imidazoline scaffold, considering the documented success in the development of numerous biologically active compounds acting outside of the α/I receptor domain.

Potent, orally available, selective COX-2 inhibitors based on 2-imidazoline core.

A novel series of compounds containing a polar, non-flat 2-imidazoline core was designed based on the SAR information available for aromatic azole cyclooxygenase-2 inhibitors. While the majority of the compounds prepared using an earlier developed imidazoline N-arylation methodology turned out to be inferior to the known COX-2 inhibitors, one lead compound displayed potency (300 nM) comparable to clinically used Celecoxib and was shown to be more selective. The series represents the first example of selective COX-2 inhibitors built around a distinctly polar core, contradicting an earlier accepted view that a lipophilic scaffold is required for high inhibitor potency.