SELECTIVE ESTROGEN RECEPTOR MODULATORS; ROLE OF SIDE CHAIN IN ACTIVITY MODULATION

Selective estrogen receptor modulators (SERMs) are a class of molecules that activate estrogen receptors (ER), impacting differently on differenttissues. Upon binding to ER, the ligand-receptor complex may present various conformations due to the presence of two different kinds of ERs. Fewof these ligands show estrogenic effects, whereas others will inhibit the action of estrogens. Researchers are working in the direction to generatethe SERMs that have a desirable estrogen-like effects on the various sites i.e., bones, improving lipid profile, reduce hot flushes, but do not act likeestrogens in unwanted ways i.e., causing breast cancer, uterine endometrial proliferation. Given the comprehensive nature of this article, it is not ourintention to revisit many of the issues relating to SERMs, which have already been covered in detail. Rather this article focuses on the aspect thatligand-mediated structural perturbations in and around the ligand binding pocket, contributed by the side chain effects lead to receptor antagonism.Adjusting the balance of these effects may provide a novel strategy for designing of improved SERMs. In the light of this, the article will provide anoverview of the SERMs and their structural diversity.Keywords: Ligand and estrogen receptor, Side chain of selective estrogen receptor modulators, Selective estrogen receptor modulators, Mechanismof action

Anti-thrombotic efficacy of S007-867: Pre-clinical evaluation in experimental models of thrombosis in vivo and in vitro.

Pharmacological inhibition of platelet collagen interaction is a promising therapeutic strategy to treat intra-vascular thrombosis. S007-867 is a novel synthetic inhibitor of collagen-induced platelet aggregation. It has shown better antithrombotic protection than aspirin and clopidogrel with minimal bleeding tendency in mice. The present study is aimed to systematically investigate the antithrombotic efficacy of S007-867 in comparison to aspirin and clopidogrel in vivo and to delineate its mechanism of action in vitro. Aspirin, clopidogrel, and S007-867 significantly reduced thrombus weight in arterio-venous (AV) shunt model in rats. In mice, following ferric chloride induced thrombosis in either carotid or mesenteric artery; S007-867 significantly prolonged the vessel occlusion time (1.2-fold) and maintained a sustained blood flow velocity for >30 min. Comparatively, clopidogrel showed significant prolongation in TTO (1.3-fold) while aspirin remained ineffective. Both S007-867 and aspirin did not alter bleeding time in either kidney or spleen injury models, and thus maintained hemostasis, while clopidogrel showed significant increase in spleen bleeding time (1.7-fold). The coagulation parameters namely thrombin time, prothrombin time or activated partial thromboplastin time remained unaffected even at high concentration of S007-867 (300 µM), thus implying its antithrombotic effect to be primarily platelet mediated. S007-867 significantly inhibited collagen-mediated platelet adhesion and aggregation in mice ex-vivo. Moreover, when blood was perfused over a highly thrombogenic combination of collagen mimicking peptides like CRP-GFOGER-VWF-III, S007-867 significantly reduced total thrombus volume or ZV50 (53.4 ± 5.7%). Mechanistically, S007-867 (10-300 μM) inhibited collagen-induced ATP release, thromboxane A2 (TxA2) generation, intra-platelet [Ca+2] flux and global tyrosine phosphorylation including PLCγ2. Collectively the present study highlights that S007-867 is a novel synthetic inhibitor of collagen induced platelet activation, that effectively maintains blood flow velocity and delays vascular occlusion. It inhibits thrombogenesis without compromising hemostasis. Therefore, S007-867 may be further developed for the treatment of thrombotic disorders in clinical settings

Synthesis of N-[3'-(acetylthio)alkanoyl] and N-[3'-mercaptoalkanoyl]-4-α (s)-(phenylmethyl) pyroglutamic acids and prolines as potent ACE inhibitors

Angiotensin converting enzyme (ACE) inhibitors have emerged as a revolution in antihypertensive therapy. Introduction of captopril, the first rationally designed ACE inhibitor, has encouraged researchers all over the world to design and synthesize target molecules controlling hypertension based on these lines. It has been observed that replacing proline part of captopril with 4-substituted prolines or 5-oxo-prolines led to significant enhancement in ACE inhibitory activity, and this observation prompted us to design and synthesize N-acyl 4-substituted pyroglutamates and prolinates with the objective of developing therapeutically better ACE inhibitors. Herein we describe an easy approach for N-acylation of 4-α (S)-(phenylmethyl) pyroglutamates with the aim of synthesizing N-[3'-(acetylthio)alkanoyl] and N-[3'-mercaptoalkanoyl]-4-α -(s)-(phenylmethyl) pyroglutamic acids and prolines as ACE inhibitors

A new method for the synthesis of ethyl (1α, 5α<i>, </i>6α)-3-benzyl-3-azabicyclo[3.1.0.]hexane-2,4-dione-6-carboxylate: An intermediate for the trovafloxacin side chain^$

873-875A convenient and high yield process for ethyl (1α, 5α, 6α)-3-benzyl-3-azabicyclo[3.1.0.]hexane-2,4-dione-6-carboxylate using a facile endo-exo conversion by DBU is described

Collinsella aerofaciens linked with increased ethanol production and liver inflammation contribute to the pathophysiology of NAFLD

Summary: Non-alcoholic fatty liver disease (NAFLD) is an emerging global health problem and a potential risk factor for metabolic diseases. The bidirectional interactions between liver and gut made dysbiotic gut microbiome one of the key risk factors for NAFLD. In this study, we reported an increased abundance of Collinsella aerofaciens in the gut of obese and NASH patients living in India. We isolated C. aerofaciens from the fecal samples of biopsy-proven NASH patients and observed that their genome is enriched with carbohydrate metabolism, fatty acid biosynthesis, and pro-inflammatory functions and have the potency to increase ethanol level in blood. An animal study indicated that mice supplemented with C. aerofaciens had increased levels of circulatory ethanol, high levels of hepatic hydroxyproline, triglyceride, and inflammation in the liver. The present findings indicate that perturbation in the gut microbiome composition is a key risk factor for NAFLD

Automated versus physician assignment of cause of death for verbal autopsies: randomized trial of 9374 deaths in 117 villages in India

Abstract Background Verbal autopsies with physician assignment of cause of death (COD) are commonly used in settings where medical certification of deaths is uncommon. It remains unanswered if automated algorithms can replace physician assignment. Methods We randomized verbal autopsy interviews for deaths in 117 villages in rural India to either physician or automated COD assignment. Twenty-four trained lay (non-medical) surveyors applied the allocated method using a laptop-based electronic system. Two of 25 physicians were allocated randomly to independently code the deaths in the physician assignment arm. Six algorithms (Naïve Bayes Classifier (NBC), King-Lu, InSilicoVA, InSilicoVA-NT, InterVA-4, and SmartVA) coded each death in the automated arm. The primary outcome was concordance with the COD distribution in the standard physician-assigned arm. Four thousand six hundred fifty-one (4651) deaths were allocated to physician (standard), and 4723 to automated arms. Results The two arms were nearly identical in demographics and key symptom patterns. The average concordances of automated algorithms with the standard were 62%, 56%, and 59% for adult, child, and neonatal deaths, respectively. Automated algorithms showed inconsistent results, even for causes that are relatively easy to identify such as road traffic injuries. Automated algorithms underestimated the number of cancer and suicide deaths in adults and overestimated other injuries in adults and children. Across all ages, average weighted concordance with the standard was 62% (range 79–45%) with the best to worst ranking automated algorithms being InterVA-4, InSilicoVA-NT, InSilicoVA, SmartVA, NBC, and King-Lu. Individual-level sensitivity for causes of adult deaths in the automated arm was low between the algorithms but high between two independent physicians in the physician arm. Conclusions While desirable, automated algorithms require further development and rigorous evaluation. Lay reporting of deaths paired with physician COD assignment of verbal autopsies, despite some limitations, remains a practicable method to document the patterns of mortality reliably for unattended deaths. Trial registration ClinicalTrials.gov , NCT02810366. Submitted on 11 April 2016