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Protease-activated receptor 4 (PAR4) is a G-protein coupled receptor that is expressed on human platelets and activated by the coagulation enzyme thrombin. PAR4 plays a key role in blood coagulation, and its importance in pathological thrombosis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of imidazothiadiazole PAR4 antagonists to a first-in-class clinical candidate, BMS-986120 (

A practical and scalable route to (3aR, 9bR)-8-fluoro-7-(perfluoropropan-2-yl)-9b-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole 10, an advanced intermediate en route to the synthesis o...

Recent mouse knockout studies identified adapter protein-2 associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. Potent small-molecule inhibitors of AAK1 have been identified and show efficacy in various rodent pain models. (

A scalable route to the small molecule TGFβR1 inhibitor BMS-986260 (1) was developed. This alternative approach circumvented the purification of intermediates by column chromatography and provided ...

[Image: see text] Novel imidazole-based TGFβR1 inhibitors were identified and optimized for potency, selectivity, and pharmacokinetic and physicochemical characteristics. Herein, we report the discovery, optimization, and evaluation of a potent, selective, and orally bioavailable TGFβR1 inhibitor, 10 (BMS-986260). This compound demonstrated functional activity in multiple TGFβ-dependent cellular assays, excellent kinome selectivity, favorable pharmacokinetic properties, and curative in vivo efficacy in combination with anti-PD-1 antibody in murine colorectal cancer (CRC) models. Since daily dosing of TGFβR1 inhibitors is known to cause class-based cardiovascular (CV) toxicities in preclinical species, a dosing holiday schedule in the anti-PD-1 combination efficacy studies was explored. An intermittent dosing regimen of 3 days on and 4 days off allowed mitigation of CV toxicities in one month dog and rat toxicology studies and also provided similar efficacy as once daily dosing.

We describe the synthesis through visible-light photocatalysis of novel functionalized tetracyclic scaffolds that incorporate a fused azabicyclo[3.2.0]heptan-2-one motif, which are structurally interesting cores with potential in natural product synthesis and drug discovery. The synthetic approach involves an intramolecular [2 + 2] cycloaddition with concomitant dearomatization of the heterocycle via an energy transfer process promoted by an iridium-based photosensitizer, to build a complex molecular architecture with at least three stereogenic centers from relatively simple, achiral precursors. These fused azabicyclo[3.2.0]heptan-2-one-based tetracycles were obtained in high yield (generally >99%) and with excellent diastereoselectivity (>99:1). The late-stage derivatization of a bromine-substituted, tetracyclic indoline derivative with alkyl groups, employing a mild Negishi C-C bond forming protocol as a means of increasing structural diversity, provides additional modularity that will enable the delivery of valuable building blocks for medicinal chemistry. Density functional theory calculations were used to compute the T1-S0 free energy gap of the olefin-tethered precursors and also to predict their reactivities based on triplet state energy transfer and transition state energy feasibility.

RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.

A scalable route to 1-(5-(4-(3-hydroxy-3-methylbutyl)-1H-1,2,3-triazol-1-yl)-4-(isopropylamino)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (1, BMS-986236) was developed by incorporating an alternate azide intermediate following safety-driven processes. The newly developed process involved mitigating safety hazards and eliminating the column chromatography purification. The issue of trace metal contamination in the final API observed in the first-generation synthesis has been overcome.

A facile, DAST-mediated intramolecular cyclization of 3-hydroxy-3-(2-((3-methoxybenzyl)oxy)phenyl)indolin-2-one derivatives for the synthesis of spirooxindoles fused with dibenzoxepine moieties is described. The success of this reaction is highly dependent on the choice of solvent (promoted by DCM and 1,2-DCE) and the electronic nature of the pendant aromatic ring, which is favored by the presence of electron-donating substituents. The reaction is believed to proceed through an intramolecular Friedel–Crafts-type reaction. Various dibenzoxepine-fused spirooxindoles were successfully synthesized in up to 98% yield. This methodology provides libraries of structurally diverse and medicinally important small molecules that could aid in the search for new bioactive molecules.

Analysis and purification of boronic acid pinacol esters by RPLC is very challenging due to their degradation in aqueous and alcoholic solvents. These compounds are difficult to purify by SFC too as they are equally sensitive to traditional co-solvents like methanol, ethanol, and 2-propanol. 2,2,2 trifluoroethanol (TFE), which has been reported for the purification of a few alcohol sensitive compounds, was evaluated as a co-solvent in this study for the purification of chiral and achiral boronate esters by SFC. Examples of twelve compounds were presented in this paper where degradation of boronic acid pinacol esters was successfully controlled by replacing methanol with TFE as the co-solvent in SFC. A separate study showed that TFE can also control the epimerization of the enantiomers of 3 substituted 1,4 benzodiazepine analogues during the purification process. In addition to above benefits, 2,2,2trifloroethanol showed improved selectivity and resolution for most of the compounds. With its stronger solvent strength compared to other alcohols, TFE could also be used to reduce the co-solvent percentage needed for elution and to shorten retention time of highly polar samples which did not elute even in 50% of other co-solvents in SFC. A case study of compound B demonstrated that TFE provided a reduced co-solvent percentage and a shorter cycle time with much improved resolution as compared to methanol, thus resulting in higher loading and throughput with reduction of total solvent consumption.

Nature employs specialized macromolecules to produce highly complex structures and understanding the role of these macromolecules allows us to develop novel materials with interesting properties. Herein, we report the role of modified conjugated polymers in the nucleation, growth, and morphology of calcium carbonate (CaCO 3 ) crystals. In situ incorporation of sulfonated poly(p-phenylene) (s(PPP)) into a highly oriented calcium carbonate matrix is investigated along with the synthesis and patterning of luminescent CaCO 3 -PPP hybrid materials. Functionalized PPP with polar and nonpolar groups are used as additives in the mineralization medium. The polymer (P1) with polar groups give iso-oriented calcite crystals, whereas PPP with an additional alkyl chain (P2) results in vaterite crystals. The crystallization mechanism can be explained based on self-assembly and aggregation of polymers in an aqueous environment. Such light-emitting hybrid composites with tunable optical properties are excellent candidates for optoelectronics and biological applications.

A series of conjugated poly(p-phenylene carbazole) copolymers, poly(N-hexyl-3,6-carbazole-alt-2,5-bisdodecyloxyphenylene) [P1], poly(N-ethylhexyl-3,6-carbazole-alt-2,5-bisdodecyloxyphenylene) [P2], and poly(N-dodecyl-3,6-carbazole-alt-2,5-bisdodecyloxyphenylene) [P3] were prepared by using palladium-catalyzed Suzuki coupling reactions. All copolymers were characterized by means of FT-IR, GPC, 1H and 13C NMR, UV−vis, fluorescence spectroscopy, and X-ray powder diffraction patterns. All copolymers were soluble in common organic solvents, exhibited good thermal stability up to 390 °C, and showed UV−vis absorbance and fluorescence maxima around 328 and 394 nm, respectively. The polymers P1−P3 differed in N-alkyl substitution, i.e., n-hexyl (for P1), n-ethylhexyl (for P2), and n-dodecyl (for P3) groups. In addition, a third monomer, 2,5-substituted pyridine for poly(N-ethylhexyl-3,6-carbazole-co-2,5-didodecyloxy phenylene-co-2,5-pyridine) (P4) and dialkylated fluorene for poly(N-ethylhexyl-3,6-carbazole-co-2,5...

Sodium salts of water-soluble polymers poly{[2,5-bis(3-sulfonatopropoxy)-1,4-phenylene]-alt-[2,5-bis(hexyloxy)-1,4-phenylene]} (P1), poly{[2,5-bis(3-sulfonatopropoxy)-1,4-phenylene]-alt-[2,5-bis(dodecyloxy)-1,4-phenylene]} (P2), poly{[2,5-bis(3-sulfonatopropoxy)-1,4-phenylene]-alt-[2,5-bis(dibenzyloxy)-1,4-phenylene]} (P3), poly[2-hexyloxy-5-(3-sulfonatopropoxy)-1,4-phenylene] (P4), and poly[2-dodecyloxy-5-(3-sulfonatopropoxy)-1,4-phenylene] (P5)] were synthesized with Suzuki coupling reactions and fully characterized. The first group of polymers (P1–P3) with symmetric structures gave lower absorption maxima [maximum absorption wavelength (λmax) = 296–305 nm] and emission maxima [maximum emission wavelength (λem) = 361–398 nm] than asymmetric polymers P4 (λmax = 329 nm, λem = 399 nm) and P5 (λmax = 335 nm, λem = 401 nm). The aggregation properties of polymers P1–P5 in different solvent mixtures were investigated, and their influence on the optical properties was examined in detail. Dynamic light scattering studies of the aggregation behavior of polymer P1 in solvents indicated the presence of aggregated species of various sizes ranging from 80 to 800 nm. The presence of alkoxy groups and 3-sulfonatopropoxy groups on adjacent phenylene rings along the polymer backbone of the first set hindered the optimization of nonpolar interactions. The alkyl chain crystallization on one side of the polymer chain and the polar interactions on the other side allowed the polymers (P4 and P5) to form a lamellar structure in the polymer lattice. Significant quenching of the polymer fluorescence upon the addition of positively charged viologen derivatives or cytochrome-C was also observed. The quenching effect on the polymer fluorescence confirmed that the newly synthesized polymers could be used in the fabrication of biological and chemical sensors. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 3763–3777, 2006

The combination of microfabrication and reaction engineering techniques has the potential to produce powerful microreactors. In a microreactor, aqueous buffers provide high electroosmatic mobility and no external pumping is required. While numerous reactions have been demonstrated to be highly efficient in microreactors, so far there has been no report on the epoxidation of cyclohexene in a microreactor. This is mainly due to the reduced solubility of cyclohexene in aqueous media. The greater volatility of cyclohexene leading to long reaction times is another reason. To improve the solubility of cyclohexene in the reaction buffer, a water soluble ionic-liquid 1-butyl-3-methylimidazolium tetrafluoroborate was used, also for the first time in microreactor work. In this letter, four different catalysts (i.e., manganese(II) and copper(II) complexes of Schiff and reduced Schiff bases) were synthesized and used for the oxidation reactions considered. The reactions were monitored by gas chromatography/mass spectrometry. The microreactor performance was evaluated by comparing with a conventional (batch scale) reaction. Catalytic activities and yields were found to be relatively high for the copper(II) complexes as compared with the conventional route.

The copper(II) complexes of the Schiff-base ligands H 2 Sams and H 2 Saes and the reduced Schiff-base ligands H 2 Sam and H 2 Sae formed between salicylaldehyde and aminomethanesulfonic acid or 2-aminoethanesulfonic acid (taurine) have been synthesized in moderate yields. The solid-state structures of the five dinuclear complexes, [Cu 2 (Sams) 2 (H 2 O 2 ] (1), [Cu 2 (Sam) 2 (H 2 O) 2 ].H 2 O (2), [Cu 2 (Saes) 2 (H 2 O) 2 ].2H 2 O (3), [Cu 2 (Sae) 2 ].2H 2 O (4), and [Cu 2 (Sae) 2 (DMF) 2 ].2DMF (5), have been determined by X-ray crystallography, showing that the Cu I I centers have distorted square-pyramidal geometry. The Schiff-base copper complexes 1 and 3 have hydrogen-bonded 2D sheet structures while the reduced Schiff-base complexes 4 and 5 display a 2D coordination network and a hydrogen-bonded 2D structure respectively. All these complexes have been investigated for their catecholase activity and activity measurements have been compared with those of dinuclear copper(II) complexes of similar ligands obtained with carboxylate analogues of the corresponding sulfonic acids; these studies show that 4 has significantly higher activity. Further, a strong antiferromagnetic interaction between Cu I I ions in dimeric complexes 1 [J = -9.04(2) cm - 1 ], 3 [J = -272(4) cm - 1 ), and 4 [J = -237(4) cm - 1 ] has been observed.

A simple glass capillary-microreactor for studying the epoxidation of cyclohexene is described in this paper. Reaction conditions were optimized to achieve high reaction yield. The microreactor is easy to fabricate, fast and easy way for reliable catalyst screening in studying homogeneous oxidation reactions. Four different catalysts (i.e. manganese(II) and copper(II) metal complexes of Schiff and reduced Schiff base ligands) were synthesized and used. The reaction products were monitored by gas chromatography/mass spectrometry. The reaction performance was compared with conventional (batch scale) reaction. In both cases, catalytic activities and the product yields were found to be relatively higher for the copper(II) complexes when compared with the conventional route.

We report for the first time the direct deposition of crystalline molybdenum sulfide (MoS2) using a single-source precursor based on tetrakis(diethylaminodithiocarbomato)molybdate(IV) (abbreviated as Mo(Et2NCS2)4). The chemistry of this precursor adsorbed on a range of substrates (silicon, germanium, gold-coated germanium, nickel, etc.) has been studied using in situ X-ray photoelectron spectroscopy. The Mo(Et2NCS2)4 precursor can be evaporated at 300 °C; its vapor adsorbs on most surfaces at room temperature and decomposes by 400 °C to form crystalline MoS2. Using this method, high-quality, basal plane-oriented MoS2 can be grown on nickel by a one-step thermal evaporation process for the first time. Interestingly, choosing elemental substrates which form eutectic alloys with gold favors the elimination of sulfur from the MoS2 film. This results in Mo intermetallic compound formation at the eutectic temperatures of the Au and substrate element. Unpredecented low-temperature growth of tetragonal MoSi2 or o...

The pyridine-containing aza-thia macrocycle 3,11,19-trithia[3.3.3]pyridinophane (10) and its complexes with NiII, PdII, CuI, AgI and HgII were synthesised and their crystal structures were determined. The NiII and HgII complexes (11, 12) are mononuclear with 10 serving as an unusual quinquedentate ligand. The CuI complex 13 is also mononuclear with 10 being tetra-coordinated to a tetrahedral CuI. Palladium(II) forms a binuclear complex 14 which exists as an inorganic zwitterion and both PdII metal ions adopt the expected square-planar geometry with facial coordination. Silver(I) forms one-dimensional coordination polymers (15 and 16) with 10 and these exhibit two different coordination modes, namely tetrahedral and trigonal planar. It was found that the macrocycle 10 did not show any selectivity among a series of metal ions. The electronic and redox properties of several complexes were studied. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

An aza-oxa-thia macrocycle, 5,14-dioxa-2,17-dithia[6](1,2)benzeno[6](2,6)pyridinophane, L1, the related smaller macrocycle 2,14-dithia-11-oxa-[3](1,2)benzeno[6](2,6)pyridinophane, L2, and the complexes with Pd(II) and Cu(II) of the macrocycle, L1, have been synthesized. The crystal structure of L2 and those of the two metal complexes have been determined. In the complexes, the metal ions adopt exclusively square planar geometry in which the pyridine nitrogen, two sulfurs and one chlorine atom are coordinated and there is no appreciable interaction with the oxygen donors. Thus, the `hard–soft acid–base' principle is illustrated by the behaviour of L1. The structures of both complexes are compared with the previously reported mixed aza-thia macrocycle, 2,5,14,17-tetrathia[6](1,2)benzeno[6](2,6)pyridinophane. The crystal structure of the smaller macrocycle, L2, is also discussed and due to the nature of its smaller cavity, attempts to make complexes with it have not been successful.

A number of dicopper(II) complexes of reduced Schiff base ligands, N-(2-hydroxybenzyl)-amino acids [Cu2L2(H2O)x]·yH2O (L = Sgly (1), D-Sala (2), L-Sala (3), DL-Sala (4), Sab2 (5), Sbal (6), Sab4 (7), Sval (8), Shis (9), Styr (10) and Stryp (11), x = 0–2 & y = 0–2) have been synthesized, and the solid-state structures of 4, 5,10 and 11 have been determined. The compounds 4 and 5 are binuclear in which the Cu(II) centres have square-pyramidal geometry with apical sites occupied by aqua ligands. In 10 and 11 one axial site is occupied by water and the other by an oxygen atom of the carboxylate group from the adjacent dimer through oxygen atoms to form 1D helical polymer. Variable temperature magnetic measurements of the dimer 4 and helical polymer 10 showed that they are typical for moderately strong antiferromagnetic coupling. All the complexes show significant catalytic activity on the oxidation of 3,5-di-tert-butylcatechol. The activity measured in terms of Kcat in the range 199–3800 h−1 has been found to follow the order: 7 > 6 > 8 > 3 > 5 ∼ 2 ∼1 > 4 > 10 >9 > 11. The catalytic activity is found to increase with increasing the length of the methylene side chain of the amino acid in the reduced Schiff base ligands.

Well-organized structures of polymers in thin films have been widely investigated. Amphiphilic polymers, star-shaped polymers and modified polystyrene-based polymers have been shown to form self-assembled honeycomb patterns on substrates. Herein, we report a poly (p-phenylene) derivative capable of producing self-assembled regular structures. Highly fluorescent honeycomb structures were observed on various substrates. The nature of the substrate and polymer influences the morphology of the film.

Porous polypropylene hollow fiber membrane coated with a conjugated polymer was used as an on-site sampling device for the extraction of polychlorinated biphenyls and polybrominated biphenyl ethers from coastal sea water samples. The coated hollow fiber membrane was placed in a vial containing the sample, and the target compounds extracted via manual shaking of the vials at the site of sample collection. For each extraction, two fibers were used. After extraction, the fibers with the adsorbed analytes were brought back to the laboratory for further processing. Care was taken to preserve the integrity of the analytes and to avoid contamination during transport; after extraction, the fibers were carefully removed and placed in air-tight crimper vials which were stored in an ice-box. The analytes were desorbed by solvent in the laboratory and analyses were carried out using gas chromatography/mass spectrometry. This method was highly reproducible with relative standard deviations in the range of 1–9%. Recoveries from spiked water samples ranged from 83% to 98%. Low limits of detections between 0.04 and 0.21 ng l −1 were achieved. The extraction efficiency was compared with solid-phase microextraction.

[structure: see text]. An X-ray crystallographic study of zinc(II) 5,15-di-(2-methoxymethylphenyl)-porphyrin indicates that it forms a coordination polymer through ligation of the ether oxygen atoms on the porphyrin peripheries to the metal centers of two identical adjacent porphyrins. This gives a novel extensively linked, three-dimensional polymeric structure in which the zinc(II) metal forms a six-coordination center. The uniquely structured network has cavities between 4.81 and 9.27 angstroms, which makes it resemble molecular sieve materials.