Quality by design (QbD) of amide isosteres: 5,5-Disubstituted isoxazolines as potent CRTh2 antagonists with favorable pharmacokinetic and drug-like properties.

Isoxazoles are frequently used amide isosteres, as shown in the context of discovery of CRTh2 antagonists from amide 1 to isoxazole 2. However, persistent agonism and poor solubility in isoxazole series presented challenges to its further development. Based on the concept of quality by design (QbD), 5,5-disubstituted isoxazolines 3 were introduced. The chirality at 5 position of isoxazolines controlled the switch between two modes of actions, which led to a novel series of pure antagonists. This non-planar motif also conferred a change of shape of these molecules, which avoided flat structures and improved their physical properties.

The discovery of fused oxadiazepines as gamma secretase modulators for treatment of Alzheimer's disease.

In an attempt to further improve overall profiles of the oxadiazine series of GSMs, in particular the hERG activity, conformational modifications of the core structure resulted in the identification of fused oxadiazepines such as 7i which had an improved hERG inhibition profile and was a highly efficacious GSM in vitro and in vivo in rats. These SAR explorations offer opportunities to identify potential drugs to treat Alzheimer's disease.

Discovery of fused 5,6-bicyclic heterocycles as γ-secretase modulators.

We herein report the discovery of four series of fused 5,6-bicyclic heterocycles as γ-secretase modulators. Synthesis and SAR of these series are discussed. These compounds represent a new class of γ-secretase modulators that demonstrate moderate to good in vitro potency in inhibiting Aß(42) production.

Rhodium-catalyzed addition of alkynes to activated ketones and aldehydes.

[reaction: see text] The rhodium-catalyzed addition of alkynes to 1,2-diketones, 1,2-ketoesters, and aldehydes provides a method for the synthesis of tertiary alkynyl alcohols under mild conditions. The reaction tolerates many functional groups (such as carboxylic acids) that are incompatible with other methods. The alkyne addition reaction proceeds best using bulky phosphine ligands such as 2-(di-tert-butylphosphino)biphenyl. This method fills a void in the more common zinc-catalyzed processes, which give poor yields with enolizable 1,2-dicarbonyl substrates.

Discovery of a Potent Dihydrooxadiazole Series of Non-ATP-Competitive MK2 (MAPKAPK2) Inhibitors.

Inhibition of MK2 has been shown to offer advantages over that of p38 MAPK in the development of cures for inflammatory diseases such as arthritis. P38 MAPK knockout in mice was lethal, whereas MK2-null mice demonstrated strong inhibition of disease progression in collagen-induced arthritis and appeared normal and viable. However, it is challenging to develop ATP-competitive MK2 inhibitors due to high ATP binding affinity to the kinase. Non-ATP-competitive MK2 inhibitors interact and bind to the kinase in a mode independent of ATP concentration, which could provide better selectivity and cellular potency. Therefore, it is desirable to identify non-ATP-competitive MK2 inhibitors. Through structure optimization of lead compound 1, a novel series of dihydrooxadiazoles was discovered. Additional structure-activity relationship (SAR) study of this series led to the identification of compound 38 as a non-ATP-competitive MK2 inhibitor with potent enzymatic activity and good cellular potency. The SAR, synthesis, and biological data of dihydrooxadiazole series are discussed.

Discovery of a Potent Pyrazolopyridine Series of γ-Secretase Modulators.

The synthesis and structure-activity relationship of a novel series of pyrazolopyridines are reported. These compounds represent a new class of γ-secretase modulators that demonstrate good in vitro potency in inhibiting Aß42 production. Examples with statistically significant in vivo efficacy in reducing the production of rat cerebrospinal fluid Aß42 were also identified.

Addition of alkynes to aldehydes and activated ketones catalyzed by rhodium-phosphine complexes.

A mixture of 2-(di-tert-butylphosphino)biphenyl and dicarbonylacetonato rhodium(I) provides an effective catalyst system for the addition of alkynes to aldehydes and activated ketones. In contrast to the more common zinc-catalyzed processes, enolizable 1,2-dicarbonyls are excellent substrates for these rhodium-catalyzed additions. This reaction allows for the formation of propargylic alcohols under mild conditions, tolerating many functional groups (such as carboxylic acids) that are incompatible with other methods. Little selectivity was observed in cases of unsymmetrical 1,2-diketones. Addition of alkynes to aldehydes with an adjacent chirality center usually provides the Felkin addition product with excellent selectivity in some cases. Studies on the catalyst structure show that both the beta-diketonate and a carbon monoxide ligand appear to be bound to the active catalyst. The use of chiral phosphines to induce asymmetry in the propargyl alcohol products provided low enantioselectivity, which may be due to the phosphine having a distal relationship to the reacting centers. Modification of other ligands, such as the beta-diketonate, appears to be a more promising avenue for the development of an enantioselective variant.