Discovery of BMS-986308: A Renal Outer Medullary Potassium Channel Inhibitor for the Treatment of Heart Failure.

Recent literature reports highlight the importance of the renal outer medullary potassium (ROMK) channel in renal sodium and potassium homeostasis and emphasize the potential impact that ROMK inhibitors could have as a novel mechanism diuretic in heart failure patients. A series of piperazine-based ROMK inhibitors were designed and optimized to achieve excellent ROMK potency, hERG selectivity, and ADME properties, which led to the identification of compound (BMS-986308). BMS-986308 demonstrated efficacy in the volume-loaded rat diuresis model as well as promising in vitro and in vivo profiles and was therefore advanced to clinical development.

Structure-Property Basis for Solving Transporter-Mediated Efflux and Pan-Genotypic Inhibition in HCV NS5B Inhibitors.

In solving the P-gp and BCRP transporter-mediated efflux issue in a series of benzofuran-derived pan-genotypic palm site inhibitors of the hepatitis C virus NS5B replicase, it was found that close attention to physicochemical properties was essential. In these compounds, where both molecular weight (MW >579) and TPSA (>110 Å) were high, attenuation of polar surface area together with weakening of hydrogen bond acceptor strength of the molecule provided a higher intrinsic membrane permeability and more desirable Caco-2 parameters, as demonstrated by trifluoroacetamide and the benchmark -ethylamino analog . In addition, the tendency of these inhibitors to form intramolecular hydrogen bonds potentially contributes favorably to the improved membrane permeability and absorption.

Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies.

The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile.

[1, 2, 4]-oxadiazoles: synthesis and biological applications.

In the present article synthesis and medicinal applications of [1, 2, 4] oxadiazoles are reviewed. The oxadiazoles have a wide range of applications such as Antitussive, Anti-inflammatory, Anaesthetic, Vasodilator, anthelmintic, antiallergic, antiplatelet effects in vitro, antithrombotic properties in vivo, etc. Many researchers have synthesized novel heterocyclic compounds containing oxadiazoles with the concept of bioisosterism.

Synthesis of novel bioactive derivatives of 3-(4-chlorophenyl)-2-hydrazino-5,6,7,8-tetrahydrobenzo(b)thieno[2,3-d]pyrimidine-4(3H)-ones.

A series of triazolo[4,3-a]tetrahydrobenzo(b)thieno[3,2-e]pyrimidine-5(4H)-ones (12a-n) were synthesized and evaluated for CNS depressant, skeletal muscle relaxant and anticonvulsant activities by photoactometer, Rotarod and pentylenetetrazole induced the convulsions method respectively in Swiss albino mice. Diazepam was used as standard drug. The five derivatives 12b, 12c, 12d, 12i and 12m showed the CNS depressant and skeletal muscle relaxant activities comparable to those of diazepam at a dose of 5mg/kg.

Synthesis, analgesic and anti-inflammatory activities of novel 3-(4-acetamido-benzyl)-5-substituted-1,2,4-oxadiazoles.

A series of 3-(4-acetamido-benzyl)-5-substituted-1,2,4-oxadiazoles (7a-7n) were synthesized and screened for analgesic and in vivo anti-inflammatory activities using acetic acid writhing in mice model and carrageenan-induced paw oedema method in mice, respectively. The analgesic activity of compounds 7i and 7m is superior while that of 7d, 7c, 7f and 7j is equal to the reference standard, diclofenac sodium. The anti-inflammatory activity of compounds 6, 7c, 7e, 7f, 7i, 7l, 7m and 7n is found to be superior than that of diclofenac sodium which is used as a reference, while compounds 7d and 7g are found to be equipotent with the reference compound.