Preferential crystallization of (±)-pinenyllithium·TMEDA.

(±)-Pinenyllithium·TMEDA or (tetramethylethylenediamine-κN,N')(η-6,6-dimethyl-2-methylenebicyclo[3.1.1]heptyl)lithium, [Li(CH)(CHN)], is readily prepared from β-pinene, butyllithium and TMEDA, and the racemic material preferentially crystallizes even from 96:4 (92% ee) mixtures of (-)- and (+)-β-pinene, respectively.

3,4-Diaza-bicyclo[4.1.0]hept-4-en-2-one phenoxypropylamine analogs of irdabisant (CEP-26401) as potent histamine-3 receptor inverse agonists with robust wake-promoting activity.

A novel series of 3,4-diaza-bicyclo[4.1.0]hept-4-en-2-ones were designed and synthesized as H3R analogs of irdabisant 6.

Piperidine-3,4-diol and piperidine-3-ol derivatives of pyrrolo[2,1-f][1,2,4]triazine as inhibitors of anaplastic lymphoma kinase.

The diastereoselective synthesis and biological activity of piperidine-3,4-diol and piperidine-3-ol-derived pyrrolotriazine inhibitors of anaplastic lymphoma kinase (ALK) are described. Although piperidine-3,4-diol and piperidine-3-ol derivatives showed comparable in vitro ALK activity, the latter subset of inhibitors demonstrated improved physiochemical and pharmacokinetic properties. Furthermore, the stereochemistry of the C3 and C4 centers had a marked impact on the in vivo inhibition of ALK autophosphorylation.

Discovery of an orally efficacious inhibitor of anaplastic lymphoma kinase.

Anaplastic lymphoma kinase (ALK) is a promising therapeutic target for the treatment of cancer, supported by considerable favorable preclinical and clinical activities over the past several years and culminating in the recent FDA approval of the ALK inhibitor crizotinib. Through a series of targeted modifications on an ALK inhibitor diaminopyrimidine scaffold, our research group has driven improvements in ALK potency, kinase selectivity, and overall pharmaceutical properties. Optimization of this scaffold has led to the identification of a potent and efficacious inhibitor of ALK, 25b.

4-phenoxypiperidine pyridazin-3-one histamine H(3) receptor inverse agonists demonstrating potent and robust wake promoting activity.

Structure-activity relationships for a series of phenoxypiperidine pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. The search for compounds with improved hERG and DAT selectivity without the formation of in vivo active metabolites identified 6-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-4,4-dimethyl-4,5-dihydro-2H-pyridazin-3-one 17b. Compound 17b met discovery flow criteria, demonstrated potent H(3)R functional antagonism in vivo in the rat dipsogenia model and potent wake activity in the rat EEG/EMG model at doses as low as 0.

Design, synthesis, and anaplastic lymphoma kinase (ALK) inhibitory activity for a novel series of 2,4,8,22-tetraazatetracyclo[14.3.1.1³,⁷.1⁹,¹³]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene macrocycles.

A novel set of 2,4,8,22-tetraazatetracyclo[14.3.1.

Structure activity relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one cathepsin K inhibitors.

The syntheses, in vitro characterizations, and rat and monkey in vivo pharmacokinetic profiles of a series of 5-, 6-, and 7-methyl-substituted azepanone-based cathepsin K inhibitors are described. Depending on the particular regiochemical substitution and stereochemical configuration, methyl-substituted azepanones were identified that had widely varied cathepsin K inhibitory potency as well as pharmacokinetic properties compared to the 4S-parent azepanone analogue, 1 (human cathepsin K, K(i,app) = 0.16 nM, rat oral bioavailability = 42%, rat in vivo clearance = 49.

Synthesis, structural and spectroscopic characterization, catalytic properties, and thermal transformations of new cyclic di- and trisiloxanediolato tantalum complexes.

The reaction between Ta(OEt)5 and 1,1,3,3-tetramethyl-1,3-disiloxanediol, (HOSiMe2OSiMe2OH), leads to new siloxy complexes in which the dimeric nature of Ta(OEt)5 is maintained with both bridging ethoxide and disiloxanediolato bridges. With equal amounts of the reagents, two terminal OEt groups are replaced to form [Ta(OEt)2]2(mu-OEt)2(mu-OSiMe2OSiMe2O)2, 1, whereas with an excess of diol, the remaining terminal OEt groups are also replaced but with a trisiloxanediolato unit to form [Ta(OSiMe2OSiMe2OSiMe2O)]2(mu-OEt)2(mu-OSiMe2OSiMe2O)2, 2. Complexes 1 and 2 catalyze the transformation of HOSiMe2OSiMe2OH to polysiloxanes.

Solid state characterization of mometasone furoate anhydrous and monohydrate forms.

Mometasone furoate is a potent glucocorticoid anti-inflammatory agent. Its anhydrous Form 1 and monohydrate form were characterized by X-ray crystallography, X-ray powder diffraction at ambient and elevated temperature, thermal analysis, FT-IR, and dynamic moisture adsorption. In Form 1, mometasone furoate molecules pack tightly with molecules interlocked in a space group of P2(1)2(1)2(1).

Structural analysis of polymorphism and solvation in tranilast.

Five polymorphic forms of tranilast were characterized by thermal, diffractometric, and spectroscopic techniques. The crystal structures of the most stable anhydrous form (Form I), a chloroform solvate, and a dichloromethane solvate were determined from single-crystal X-ray analysis. Two additional anhydrous forms of tranilast (Forms II and III) were also studied, but were not amenable to SCXRD.

The first coordination complexes of selenones: a structural comparison with complexes of sulfones.

Reactivity of the two classes of very weak donors R(2)XO(2) (X = S, R = Me (1) and Ph (2); X = Se, R = Me (3) and Ph (4)) have been studied. Coordination properties of sulfones and selenones in solution and in the gas phase have been compared for the first time using a model bidentate metal complex, [Rh(2)(O(2)CCF(3))(4)]. Two coordination modes, bridging mu(2)-O,O' and terminal eta(1)-O, have been detected.

Phenylbutyrates as potent, orally bioavailable vitronectin receptor (integrin alphavbeta3) antagonists.

In our continuing efforts to identify small molecule vitronectin receptor antagonists, we have discovered a series of phenylbutyrate derivatives, exemplified by 16, which have good potency and excellent oral bioavailability (approximately 100% in rats). This new series is derived conceptually from opening of the seven-membered ring of SB-265123.

Design and synthesis of conformationally restricted eight-Membered ring diketones as potential serine protease inhibitors.

The design of conformationally restricted eight-membered ring diketones as transition state mimics of the mechanism of action of cyclotheonamides on serine proteases is described. Two target compounds are prepared from mutilin, derived from the natural product pleuromutilin. Compound 3 shows significant inhibition of plasmin and urokinase in enzyme rate assays, but an analogue 4 in which the amide moiety has been omitted does not.