Orchestrated triple C-H activation reactions using two directing groups: rapid assembly of complex pyrazoles.

A sequential triple C-H activation reaction directed by a pyrazole and an amide group leads to the well-controlled construction of sterically congested dihydrobenzo[e]indazole derivatives. This cascade reaction demonstrates that the often problematic competing C-H activation pathways in the presence of multiple directing groups can be harvested by design to improve step economy in synthesis. Pyrazole as a relatively weak coordinating group is shown to direct Csp3-H activation for the first time.

Discovery of novel oxazepine and diazepine carboxamides as two new classes of heat shock protein 90 inhibitors.

Two novel series of oxazepine and diazepine based HSP90 inhibitors are reported. This effort relied on structure based design and isothermal calorimetry to identify small drug like macrocycles. Computational modelling was used to build into a solvent exposed pocket near the opening of the ATP binding site, which led to potent inhibitors of HSP90 (25-30).

When structure-affinity relationships meet structure-kinetics relationships: 3-((Inden-1-yl)amino)-1-isopropyl-cyclopentane-1-carboxamides as CCR2 antagonists.

Chemokine ligand 2 (CCL2) mediates chemotaxis of monocytes to inflammatory sites via interaction with its G protein-coupled receptor CCR2. Preclinical animal models suggest that the CCL2-CCR2 axis has a critical role in the development and maintenance of inflammatory disease states (e.g., multiple sclerosis, atherosclerosis, insulin resistance, restenosis, and neuropathic pain), which can be treated through inhibition of the CCR2 receptor. However, in clinical trials high-affinity inhibitors of CCR2 have often demonstrated a lack of efficacy. We have previously described a new approach for the design of high-affinity CCR2 antagonists, by taking their residence time (RT) on the receptor into account. Here, we report our findings on both structure-affinity relationship (SAR) and structure-kinetic relationship (SKR) studies for a series of 3-((inden-1-yl)amino)-1-isopropyl-cyclopentane-1-carboxamides as CCR2 antagonists. SAR studies showed that this class of compounds tolerates a vast diversity of substituents on the indenyl ring with only small changes in affinity. However, the SKR is affected greatly by minor modifications of the structure. The combination of SAR and SKR in the hit-to-lead process resulted in the discovery of a new high-affinity and long-residence-time CCR2 antagonist (compound 15a, Ki = 2.4 nM; RT = 714 min).

Structure-kinetic relationships--an overlooked parameter in hit-to-lead optimization: a case of cyclopentylamines as chemokine receptor 2 antagonists.

Preclinical models of inflammatory diseases (e.g., neuropathic pain, rheumatoid arthritis, and multiple sclerosis) have pointed to a critical role of the chemokine receptor 2 (CCR2) and chemokine ligand 2 (CCL2). However, one of the biggest problems of high-affinity inhibitors of CCR2 is their lack of efficacy in clinical trials. We report a new approach for the design of high-affinity and long-residence-time CCR2 antagonists. We developed a new competition association assay for CCR2, which allows us to investigate the relation of the structure of the ligand and its receptor residence time [i.e., structure-kinetic relationship (SKR)] next to a traditional structure-affinity relationship (SAR). By applying combined knowledge of SAR and SKR, we were able to re-evaluate the hit-to-lead process of cyclopentylamines as CCR2 antagonists. Affinity-based optimization yielded compound 1 with good binding (Ki = 6.8 nM) but very short residence time (2.4 min). However, when the optimization was also based on residence time, the hit-to-lead process yielded compound 22a, a new high-affinity CCR2 antagonist (3.6 nM), with a residence time of 135 min.

Diastereoselective one-pot Knoevenagel condensation/Corey-Chaykovsky cyclopropanation.

Efforts to substitute the cyclopropane ring in a series of aryl cyclopropylnitriles led to the discovery of an operationally simple one-pot method for Knoevenagel condensation and subsequent Corey-Chaykovsky cyclopropanation giving diastereomerically pure products as a racemic mixture of enantiomers. Method development and results for variably substituted aryl acetonitriles and aldehydes in the reaction are reported. A concise synthesis of (±)-bicifadine in two steps is provided to demonstrate the utility of the method.