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The calcium sensing receptor (CaSR) plays an important role in maintaining calcium homeostasis. The use of calcimimetic cinacalcet has been established to activate CaSR and normalize hypercalcemia. However, cinacalcet has limitations due to its high cLogP and pKa. A systematic optimization of cinacalcet to reduce its cLogP and pKayielded compound 23a(LNP1892). Compound 23ashowed excellent potency and a favorable pharmacokinetics profile, and lacked the liabilities of cinacalcet, making it a highly differentiated precision calcimimetic. In adenine-diet-induced chronic kidney disease (CKD) models, 23ademonstrated robust and dose-dependent efficacy, as measured by plasma parathyroid hormone (PTH) levels. It also showed an excellent safety profile in animal studies. Phase 1 clinical trials with 23ain healthy volunteers confirmed its excellent safety, tolerability, and effectiveness in lowering PTH levels in a dose-dependent manner, without causing symptomatic hypocalcaemia. Encouraged by these promising results, LNP1892 was taken to a Phase 2 study in CKD patients.

The role of calcium release-activated calcium (CRAC) channels is well characterized and is of particular importance in T-cell function. CRAC channels are involved in the pathogenesis of several autoimmune diseases, making it an attractive therapeutic target for treating inflammatory diseases, like rheumatoid arthritis (RA). A systematic structure–activity relationship study with the goal of optimizing lipophilicity successfully yielded two lead compounds, 36and 37. Both compounds showed decent potency and selectivity and a remarkable pharmacokinetic profile. Further characterization in in vivo RA models and subsequent histopathological evaluation of tissues led to the identification of 36as a clinical candidate. Compound 36displayed an excellent safety profile and had a sufficient safety margin to qualify it for use in human testing. Oral administration of 36in Phase 1 clinical study in healthy volunteers established favorable safety, tolerability, and good target engagement as measured by levels of IL-2 and TNF-α.

PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a “three-blade propeller” shaped lead, 2,3-disubstituted quinolizinone 11, through a 1,2-disubstituted quinolizinone 20to a novel “four-blade propeller” shaped 1,2,3-trisubstituted quinolizinone 34. Compound 34has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound 34also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound 34qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.

Voltage-gated sodium channel NaV1.7 is a genetically validated target for pain. Identification of NaV1.7 inhibitors with all of the desired properties to develop as an oral therapeutic for pain has been a major challenge. Herein, we report systematic structure–activity relationship (SAR) studies carried out to identify novel sulfonamide derivatives as potent, selective, and state-dependent NaV1.7 inhibitors for pain. Scaffold hopping from benzoxazine to chroman and indane bicyclic system followed by thiazole replacement on sulfonamide led to identification of lead molecules with significant improvement in solubility, selectivity over NaV1.5, and CYP2C9 inhibition. The lead molecules 13, 29, 32, 43, and 51showed a favorable pharmacokinetics (PK) profile across different species and robust efficacy in veratridine and formalin-induced inflammatory pain models in mice. Compound 51also showed significant effects on the CCI-induced neuropathic pain model. The profile of 51indicated that it has the potential for further evaluation as a therapeutic for pain.

On the impingement heat transfer data, the experimental studies of air and liquid jets impingement to the flat surfaces were collected and critically reviewed. The oblique impingements of both single circular and planar slot jets were considered in particular. The review focused on the surface where the jet impingement cooling technique was utilized. The nozzle exit Reynolds numbers based on the hydraulic diameter varied in the range of 1,500–52,000. The oblique angles relative to the plane surface and the dimensionless jet-to-plate spacing vary in the range of 15°–90° and 2–12 respectively. The review suggested that the magnitude of maximum heat transfer shifted more for air jets compared with the liquid jets. The drop in the inclination angle and the jet-to-plate separation led to the increase in the asymmetry of heat transfer distribution. The displacement of maximum Nusselt number (heat transfer) locations was found to be sensitive to the inclination angle and the smaller jet-to-plate distance. Also, the Nusselt number correlations proposed by various researchers were discussed and compared with the results of the cited references.

Effective and efficient use of pesticides in the orchards is of concern since many years. With the conventional constant rate sprayers, equal dose of pesticide is applied to each tree. Since, there is great variation in size and shape of each tree in the orchard, trees gets either oversprayed or undersprayed. Real-time variable rate spraying technology offers pesticide application in accordance with tree size. With the help of suitable sensors, tree characteristics such as canopy volume, foliage density, etc. can be acquired and with the micro-processing unit coupled with proper algorithm, flow of electronic proportional valves can be controlled thus, controlling the flow rate of nozzles according to tree characteristics. Also, sensors can help in the detection of spaces in-between trees which allows to control the spray in spaces. Variable rate spraying helps in achieving precision in spraying operation especially inside orchards. This paper reviews the real-time variable rate spraying technology and efforts made by the various researchers for real-time variable application in the orchards and vineyards.

Frequency spectra obtained from the measurements of light intensity and angle of arrival (AOA) of parallel laser light propagating through the axially homogeneous, axisymmetric buoyancy-driven turbulent flow at high Rayleigh numbers in a long (length-to-diameter ratio of about 10) vertical tube are reported. The flow is driven by an unstable density difference created across the tube ends using brine and fresh water. The highest Rayleigh number is about 8×10^9. The aim of the present work is to find whether the conventional Obukhov–Corrsin scaling or Bolgiano-Obukhov (BO) scaling is obtained for the intensity and AOA spectra in the case of light propagation in a buoyancy-driven turbulent medium. Theoretical relations for the frequency spectra of log amplitude and AOA fluctuations developed for homogeneous isotropic turbulent media are modified for the buoyancy-driven flow in the present case to obtain the asymptotic scalings for the high and low frequency ranges. For low frequencies, the spectra of intensity and vertical AOA fluctuations obtained from measurements follow BO scaling, while scaling for the spectra of horizontal AOA fluctuations shows a small departure from BO scaling.