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