Discovery of LNP1892: A Precision Calcimimetic for the Treatment of Secondary Hyperparathyroidism.

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 pKa yielded compound 23a (LNP1892). Compound 23a showed 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, 23a demonstrated 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 23a in 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.

Discovery of Potent, Selective, and State-Dependent NaV1.7 Inhibitors with Robust Oral Efficacy in Pain Models: Structure-Activity Relationship and Optimization of Chroman and Indane Aryl Sulfonamides.

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 51 showed a favorable pharmacokinetics (PK) profile across different species and robust efficacy in veratridine and formalin-induced inflammatory pain models in mice. Compound 51 also showed significant effects on the CCI-induced neuropathic pain model. The profile of 51 indicated that it has the potential for further evaluation as a therapeutic for pain.

Discovery and Characterization of Potent Pan-Genotypic HCV NS5A Inhibitors Containing Novel Tricyclic Central Core Leading to Clinical Candidate.

The identification of a novel class of potent pan-genotypic NS5A inhibitors with good pharmacokinetic profile suitable for potential use in treating HCV infections is disclosed here. The present series of compounds are with less complex tricyclic central core, identified through a systematic SAR study carried out on biphenyl moiety. The SAR outcome has confirmed the requirement of near planar and linear conformation of the molecule to achieve the best pan-genotypic activity. In addition, SAR with substituted imidazoles on improvement of antiviral activity is disclosed. The newly identified compounds 12, 16, 19-21 have shown desirable pharmacokinetic profiles with a favorable uptake of compounds in liver and maintained a significant concentration for up to 8 h in the liver. In addition, compounds 20 and 21 have shown superior pan-genotypic anti-HCV activity compared to ledipasvir and daclatasvir. Additional characterization and preliminary safety assessment resulted in the identification of compound 20 as a potential clinical candidate.

Synthesis of 1-(2,6-dichlorophenyl)-3-methylene-1,3-dihydro-indol-2-one derivatives and in vitro anticancer evaluation against SW620 colon cancer cell line.

A small library of 2-indolinone derivatives with the 2,6-dichlorophenyl ring at the N(1) position and with varying substitutions including aryl groups at the 3-position were synthesized, and their structures were confirmed by spectral analysis. All molecules were screened for their in vitro cytotoxic activity on SW620 colon cancer cell lines. Among the designed series compounds 4c, 4f and 4j were found to be active at concentrations of 2-15 microg/ml. Some 3D-QSAR models were also built to understand the structure-activity relationship.

Three-dimensional quantitative structure-activity relationship of 1,4-dihydropyridines as antitubercular agents.

Three-dimensional quantitative structure-activity relationship (3D QSAR) methods, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), were applied on a series of 1,4-dihydropyridines possessing antitubercular activity. The study was performed using 33 compounds, in which 22 molecules were used for the derivation of the 3D QSAR models (training set) and 11 molecules were used to evaluate the predictive ability of the derived models (test set). Superimpositions were performed using three alignment rules: atom-based fitting, SYBYL QSAR rigid body field fit of the steric and electrostatic fields of the molecules, and flexible fitting (multifit). Both methods were analyzed in terms of their predictive abilities and produced comparable results with high internal as well as external predictivities. Steric and electrostatic fields of the inhibitors were found to be relevant descriptors for SAR. Use of lowest unoccupied molecular orbital energies or ClogP as additional descriptors in the QSAR table did not improve the significance of the 3D QSAR models. Both CoMFA and CoMSIA models based on multifit alignment showed better correlative and predictive properties than other models. A QSAR study using genetic function approximation was also performed for the same set of molecules using different types of physicochemical descriptors to deal with cell-based activity data. The QSAR models revealed the importance of spatial properties and conformational flexibility of side chains for antitubercular activity. Inclusion of fractional polar solvent accessible surface area as a descriptor in the model generation resulted in models with significant internal and external predictivities for the same test set molecules, which may support the possible mode of action of these compounds.