Effects of various bases on acid-catalyzed amination of 2-chloro-5-ethylpyrimidine: synthesis of PPARpan agonist GW693085.

A unique buffering effect of various bases, i-Pr(2)NEt and CaCO(3) in particular, was observed for the acid-catalyzed chloro displacement of 2-chloro-5-ethylpyrimidine with a 2-methyl-2-phenylpropanamine. The use of the carefully chosen bases was essential for the progression of the chloro displacement as well as the stability of the product in the presence of HCl formed. Research work leading to an efficient synthesis of PPARpan agonist GW693085 is described, featuring highly selective sequential N- and O-alkylations.

Elucidating the pathways of degradation of denagliptin.

Stress testing or forced degradation studies of denagliptin (1) tosylate in solution and solid-state, its blends with excipients, and capsules were conducted in order to elucidate degradation pathways, aid formulation development, and generate data to support regulatory filings. In solution, denagliptin was stressed in acid, water, and base using organic cosolvents. In the solid-state, denagliptin was stressed under heat, humidity, and light. Blends of denagliptin with various excipients were stressed under heat and humidity in order to evaluate whether tablet was a viable dosage form. Capsules were stressed under heat, humidity, and light. It was found that denagliptin was stable in the solid-state, but degraded in solution, in blends with all excipients, and in capsules predominantly by cyclization to (3S,7S,8aS) amidine (2), which epimerized to (3S,7S,8aR) amidine (3). (3S,7S,8aR) amidine (3) subsequently hydrolyzed to the corresponding diketopiperazine (4). The purpose of this manuscript is to discuss the results of stress testing studies conducted during the development of denagliptin and the elucidation of its key degradation pathway.

Integration of optimized substituent patterns to produce highly potent 4-aryl-pyridine glucagon receptor antagonists.

Optimized substituent patterns in 4-aryl-pyridine glucagon receptor antagonists were merged to produce highly potent derivatives containing both a 3-[(1R)-hydroxyethyl] and a 2'-hydroxy group. Due to restricted rotation of the phenyl-pyridine bond, these analogues exist as four isomers. A diastereoselective methylcopper reaction was developed to facilitate the synthesis, and single isomers were isolated with activities in the range IC(50)=10-25 nM.

Synthesis and pharmacological characterization of a potent, orally active p38 kinase inhibitor.

Inhibitors of the MAP kinase p38 provide a novel approach for the treatment of osteoporosis, inflammatory disorders, and cancer. We have identified N-(3-tert-butyl-1-methyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea as a potent and selective p38 kinase inhibitor in biochemical and cellular assays. This compound is orally active in two acute models of cytokine release (TNF-induced IL-6 and LPS-induced TNF) and a chronic model of arthritis (20-day murine collagen-induced arthritis).

Optimization of the 4-aryl group of 4-aryl-pyridine glucagon antagonists: development of an efficient, alternative synthesis.

A narrow structure-activity relationship was established for the 4-aryl group in 4-aryl-pyridine glucagon antagonists, with only small substituents being well-tolerated, and only at the 3'- and 4'-positions. However, substitution with a 2'-hydroxy group gave a ca. 3-fold increase in activity (e.g., 4'-fluoro-2'-hydroxy analogue 33, IC50=190 nM). For efficient preparation of 2'-substituted phenylpyridines, a novel synthesis via pyrones and 4-methoxy-pyridines was developed.

Tandem Dipolar Cycloaddition-Mannich Cyclization as an Approach to Tricyclic Nitrogen Heterocycles.

A series of 2-diazo-N-[2-(3,4-dimethoxyphenyl)ethyl]-N-hept-6-enoylmalonamides were prepared and treated with a catalytic amount of rhodium(II) perfluorobutyrate. The resultant carbenoids undergo facile cyclization onto the neighboring amide carbonyl oxygen atom to generate isomünchnone-type intermediates. Subsequent 1,3-dipolar cycloaddition across the pendant olefin affords intramolecular cycloadducts in high yield. Exposure of these cycloadducts to boron trifluoride etherate results in a Lewis acid-induced ring opening to generate N-acyliminium ions which then undergo Mannich cyclization onto the neighboring pi-framework attached to the amide nitrogen atom. The cis stereochemistry of the resulting A/B ring fusion is analogous to similar erythrinane products obtained via a Mondon-enamide-type cyclization. The stereochemical assignment of the final cyclized products was determined by X-ray crystallography. Molecular mechanics calculations show that the ground state energy of the cis-fused diastereomer is 4.6 kcal lower than that of the trans diastereomer, and presumably some of this thermodynamic energy difference is reflected in the transition state for cyclization. In certain cases, proton loss from the initially formed N-acyliminium ion occurs prior to cyclization to give acyl enamides which subsequently cyclize producing epimeric products.