Wavelength-tunable Tm:Y2O3 ceramic vortex laser with a changeable orbital angular momentum state.

Wavelength-tunable orbital angular momentum (OAM) lasers with controllable topological charges have the potential for serving as light sources for large-capacity optical communication by combining conventional wavelength division multiplexing (WDM) with OAM mode-division multiplexing (OAM-MDM). In this study, we demonstrate a wavelength-tunable Tm-bulk laser that can control OAM states in the 2-µm spectral range. The excitation conditions for different Laguerre-Gaussian (L G 0,l ) modes in a bulk laser cavity are theoretically determined by measuring the spatial propagation dynamics of the annular pump beam. As a proof-of-principle study, we experimentally generate OAM states of |ℏ| and |2ℏ| from a T m:Y 2 O 3 ceramic laser with a tunable emission wavelength using a Lyot filter (LF). The spatial properties of the scalar optical vortices are well conserved during wavelength tuning, indicating the feasibility of our approach for producing wavelength-tunable structured light. These OAM laser sources, which are characterized by their robustness and compactness, have potential applications in various areas such as optical communications, quantum optics, super-resolution microscopes, and more.

Reduction of depolarization loss in a Tm-doped sesquioxide ceramic laser using a ring-shaped pump beam.

We report on a simple method for reduction of the depolarization loss in an end-pumped Tm:Y2O3 ceramic laser by using a near-field ring-shaped pump beam. Initially, we theoretically derive the expression of the depolarization loss in a bulk laser end-pumped with a near-field flat-top-hat or ring-shaped beam, where a significant reduction of depolarization loss in the latter case is presented. Experimental verification is thereafter carried out with a Tm:Y2O3 ceramic laser employing these two different pump configurations. It shows that the experimentally measured depolarization losses are close to the simulated values; the loss in the case of the annular-beam pump is almost 18 times lower than that with a quasi-top-hat beam at a same absorption pump power of 7.4 W. This work, as a proof-of-principle study, indicates that depolarization loss in the end-pumped bulk lasers can be significantly reduced simply by using a ring-shaped pump beam.

Reduction of thermal effects in a 2.7-µm Er:Y2O3 ceramic laser with annular pumping.

Reduction of thermal effects is a challenging aspect for power scaling of 2.7-µm bulk Er-lasers due to the large quantum defect when pumping at ∼ 0.97 µm. Here, we demonstrate that thermal effects in an Er:Y2O3 ceramic laser can be significantly reduced pumping by an annular beam, thus improving the continuous-wave (CW) laser performance in the 3-µm spectral range. The excitation conditions of the TEM00 mode were determined theoretically by taking into account the propagation characteristics of the annular pump beam. For a comparison, the temperature and stress distributions are at first theoretically studied with three different pump configurations. In the experiment, output power of the Er:Y2O3 ceramic laser improved by ∼ 60% by changing the pump beam from coventional quasi-top-hat to a designed annular one. This work, as a proof-of-principle study, indicates the potential of power scaling of the 2.7-µm bulk Er-lasers pumping with an annular beam.

Accurate and fast narcissus calculation based on sequential ray trace.

A narcissus calculating method for cryogenic infrared imaging systems is proposed in this paper. The accuracy is largely improved compared to the traditional paraxial analysis, as ray blocking of the optical opertures is taken into account and real ray data are used during the calculation. The narcissus distribution on the full focal plane can be obtained via analyzing field by field. Meanwhile, it can be implemented simply and fast as sequential ray tracing is utilized and rays only pass through three surfaces during the cold return statistics for every retro-reflecting surface. According to this method, a general narcissus calculation package was realized using the macro language of optical design software Code V. The performance of the new method was tested by calculating an example system using this package and comparing it with traditional methods. The results showed that the new method produced the same result accuracy and information quantity as the nonsequential ray trace, while the whole analysis took only 5 s, which was significantly shortened compared with the nonsequential ray trace, which took about 30 min.

Discovery of INCB10820/PF-4178903, a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist.

We report the discovery of a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist (3S,4S)-N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-3-methoxytetrahydro-2H-pyran-4-amine (19). After evaluation in 28-day toxicology studies, compound 19 (INCB10820/PF-4178903) was selected as a clinical candidate.

Discovery of ((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone, PF-4254196, a CCR2 antagonist with an improved cardiovascular profile.

We describe the systematic optimization, focused on the improvement of CV-TI, of a series of CCR2 antagonists. This work resulted in the identification of 10 (((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone) which possessed a low projected human dose 35-45mg BID and a CV-TI=3800-fold.

Synthesis and in vivo evaluation of cyclic diaminopropane BACE-1 inhibitors.

The synthesis, evaluation, and structure-activity relationships of a set of related constrained diaminopropane inhibitors of BACE-1 are described. The full in vivo profile of an optimized inhibitor in both normal and P-gp deficient mice is compared with data generated in normal rats.

Discovery of INCB3344, a potent, selective and orally bioavailable antagonist of human and murine CCR2.

Rational design based on a pharmacophore of CCR2 antagonists reported in the literature identified lead compound 9a with potent inhibitory activity against human CCR2 (hCCR2) but moderate activity against murine CCR2 (mCCR2). Modification on 9a led to the discovery of a potent CCR2 antagonist 21 (INCB3344) with IC(50) values of 5.1 nM (hCCR2) and 9.5 nM (mCCR2) in binding antagonism and 3.8 nM (hCCR2) and 7.8 nM (mCCR2) in antagonism of chemotaxis activity. INCB3344 exhibited >100-fold selectivity over other homologous chemokine receptors, a free fraction of 24% in human serum and 15% in mouse serum, and an oral bioavailability of 47% in mice, suitable as a tool compound for target validation in rodent models.

[3H]BMS-599240--a novel tritiated ligand for the characterization of BACE1 inhibitors.

In this report we describe a novel radioligand, [(3)H](S)-2-((S)-3-Acetylamino-3-sec-butyl-2-oxo-pyrrolidin-1-yl)-N-[(1S,2R)-1-benzyl-2-hydroxy-3-(3-methoxy-benzylamino)-propyl]-4-phenyl-butyramide ([(3)H]BMS-599240), that exhibits robust specific binding in homogenates from cell cultures overexpressing beta-site amyloid precursor protein cleaving enzyme-1 (BACE1). Radioligand binding exhibited high affinity, K(d)=2 nM, commensurate with its inhibitory potency against BACE1. Inhibition of radioligand binding in the presence of a range of different BACE1 inhibitors exhibited the same rank order of potency as for inhibition of BACE1 enzymatic activity. BACE1-dependent binding of the radioligand was also demonstrated in mouse brain homogenates, where genetic ablation of BACE1 eliminated high affinity binding. Thus, the radioligand [(3)H]BMS-599240 is a novel tool potentially useful for evaluation of BACE1 enzyme in biological samples, and for evaluation of inhibitor binding to BACE1.

Discovery of CC chemokine receptor-3 (CCR3) antagonists with picomolar potency.

Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC(50) = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC(50) = 41 nM) and its oral bioavailability in mice (20% F ) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase I clinical trials.

Amidoglycosylation of Polymer-Bound Glycals: A Complete Solid-Phase Synthesis of the Oligosaccharide Domain of the Lewisb Blood Group Determinant.

A new general method for the preparation of N-acetylglucosamine glycosidic linkages has been developed for solid-phase synthesis. The complete pentasaccharide domain of the Lewisb blood group antigen, which is a mediator in the formation of ulcers and gastric cancer, has now been synthesized on solid support (see 1; the shaded circle is the polystyrene support; TIPS=triisopropylsilyl).

Discovery of INCB8761/PF-4136309, a Potent, Selective, and Orally Bioavailable CCR2 Antagonist.

We report the discovery of a new (S)-3-aminopyrrolidine series of CCR2 antagonists. Structure-activity relationship studies on this new series led to the identification of 17 (INCB8761/PF-4136309) that exhibited potent CCR2 antagonistic activity, high selectivity, weak hERG activity, and an excellent in vitro and in vivo ADMET profile. INCB8761/PF-4136309 has entered human clinical trials.

Discovery of INCB3284, a Potent, Selective, and Orally Bioavailable hCCR2 Antagonist.

We report the identification of 13 (INCB3284) as a potent human CCR2 (hCCR2) antagonist. INCB3284 exhibited an IC50 of 3.7 nM in antagonism of monocyte chemoattractant protein-1 binding to hCCR2, an IC50 of 4.7 nM in antagonism of chemotaxis activity, an IC50 of 84 µM in inhibition of the hERG potassium current, a free fraction of 58% in protein binding, high selectivity over other chemokine receptors and G-protein-coupled receptors, and acceptable oral bioavailability in rodents and primates. In human clinical trials, INCB3284 exhibited a pharmacokinetic profile suitable for once-a-day dosing (T 1/2 = 15 h).

Discovery of INCB9471, a Potent, Selective, and Orally Bioavailable CCR5 Antagonist with Potent Anti-HIV-1 Activity.

To identify a CCR5 antagonist as an HIV-1 entry inhibitor, we designed a novel series of indane derivatives based on conformational considerations. Modification on the indane ring led to the discovery of compound 22a (INCB9471) that exhibited high affinity for CCR5, potent anti-HIV-1 activity, high receptor selectivity, excellent oral bioavailability, and a tolerated safety profile. INCB9471 has entered human clinical trials.

A general method for the solid-phase synthesis of unsymmetrical tri- and tetrasubstituted ureas.

A general method for the preparation of unsymmetrical di, tri-, and tetrasubstituted ureas on polymer supports is presented. Polymer-bound primary and secondary amines react with imidazolium salts (urea donors), which are generated from the reaction of N,N'-carbonyldiimidazole (CDI) with primary and secondary amines followed by alkylation with MeI to give tri- and tetrasubstituted ureas in excellent yields (76-98%) and purities (80-99%).