Discovery of an Oxycyclohexyl Acid Lysophosphatidic Acid Receptor 1 (LPA1) Antagonist BMS-986278 for the Treatment of Pulmonary Fibrotic Diseases.

The oxycyclohexyl acid BMS-986278 (33) is a potent lysophosphatidic acid receptor 1 (LPA1) antagonist, with a human LPA1 Kb of 6.9 nM. The structure-activity relationship (SAR) studies starting from the LPA1 antagonist clinical compound BMS-986020 (1), which culminated in the discovery of 33, are discussed. The detailed in vitro and in vivo preclinical pharmacology profiles of 33, as well as its pharmacokinetics/metabolism profile, are described. On the basis of its in vivo efficacy in rodent chronic lung fibrosis models and excellent overall ADME (absorption, distribution, metabolism, excretion) properties in multiple preclinical species, 33 was advanced into clinical trials, including an ongoing Phase 2 clinical trial in patients with lung fibrosis (NCT04308681).

Diet with high content of advanced glycation end products induces systemic inflammation and weight gain in experimental mice: Protective role of curcumin and gallic acid.

The present study was aimed to investigate the effect of diet derived AGEs (dAGEs) on the circulatory levels of pro-inflammatory cytokines, chemokines and to evaluate the protective efficacy of natural anti-oxidants curcumin (CU) and gallic acid (GA) respectively against the dAGEs-induced systemic inflammation in experimental Swiss albino mice. The experimental mice were fed with dAGEs in the presence and absence of CU and GA for 6 months. The levels of 40 circulatory pro-inflammatory cytokines and chemokines were evaluated using Proteome-Cytokine Array kit. In addition, serum levels of N-ɛCML, CRP and HbA1c were estimated by ELISA method. Among the sixteen pro- and anti-inflammatory cytokines analysed, five (IL-16, IL-1α, ICAM, TIMP-1 and C5a) were found to be highly expressed (3.5-fold) and eleven cytokines were moderately expressed (2-fold) in dAGEs fed mice. In case of chemokines, three (BLC, SDF-1 and MCP-1) were found to be highly expressed (4-fold) and ten showed moderate expression (2-fold) as compared with basal diet fed mice. Interestingly, CU or GA co-treatment normalized the levels of circulatory pro- and anti-inflammatory cytokines, chemokines, N-ɛCML, CRP and HbA1c levels. Together, the present study suggests that dAGEs are positively associated with the development of systemic inflammation in experimental mice.

Valporic acid enhances the Atrial Natriuretic Peptide (ANP) mediated anti-hypertrophic activity by modulating the Npr1 gene transcription in H9c2 cells in vitro.

The present study was aimed to determine whether stimulating Npr1 gene activity using Valporic acid (VA), a small short chain fatty acid molecule can enhance ANP mediated anti-hypertrophic activity in isoproterenol (ISO) - treated H9c2 cells in vitro. H9c2 cells were treated with ISO (10-5 M) and co-treated with VA (10-5 M) in the presence and absence of ANP (10-8M), for 48h. ATRA (10-5 M) was used as a positive inducer of Npr1 gene transcription. The mRNA expression of Npr1 and PKG-I genes, proto-oncogenes (c-fos, c-jun and c-myc) and hypertrophic markers (ANP, BNP, α-sk and ß-MyHC), genes were determined by quantitative PCR (qPCR). The protein profiling of NPR-A, PKG-I and cGMP were evaluated by Western blot, immunofluorescence and ELISA respectively. A marked reduction in the level of expression of Npr1 (3- fold) and PKG-I (2.5-fold) genes and increased expression of proto-oncogenes (p< 0.001, respectively) and hypertrophic marker genes (p<0.001, respectively) were noticed in the ISO-treated H9c2 cells as compared with control cells. In contrast, the VA treated cells showed maximal Npr1 gene expression (3.5-fold) as compared with ATRA treated cells (2 fold), which is well correlated with the intracellular cGMP levels (80% vs 60%) and reduced (2.5-fold) HDAC -1&-2 mRNA expression. Furthermore, VA or ATRA treatment effectively reversed the ISO-induced altered expression of Npr1 and PKG-I genes, proto-oncogenes, and hypertrophic markers genes. Interestingly, the results of the present study suggest that ANP mediated anti-hypertrophic activity was enhanced with either VA (p<0.001) or ATRA (p<0.01) co-treatment. Together, we conclude that VA in combination with ANP can be a novel therapeutical approach for the treatment and management of left ventricular cardiac hypertrophy.