The aporetic dialogues of Modena on gender differences: Is it all about testosterone? EPISODE I: CRIME.

This is the first episode of a series of four discussions on the differences between males and females, in apparently non-andrological fields. You will read the transcript of discussions that actually took place at the Endocrinology Unit in Modena, Italy, in the form of the aporetic dialogues of ancient Greece. In this episode, the role of testosterone in gender differences in criminal behavior will be explored.

SAR evolution towards potent C-terminal carboxamide peptide inhibitors of Zika virus NS2B-NS3 protease.

Zika virus (ZIKV) is a member of the Flaviviridae family that can cause neurological disorders and congenital malformations. The NS2B-NS3 viral serine protease is an attractive target for the development of new antiviral agents against ZIKV. We report here a SAR study on a series of substrate-like linear tripeptides that inhibit in a non-covalent manner the NS2B-NS3 protease.

Discovery of (7R)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (MK-3281), a potent and orally bioavailable finger-loop inhibitor of the hepatitis C virus NS5B polymerase.

Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain.

Synthesis and SAR of piperazinyl-N-phenylbenzamides as inhibitors of hepatitis C virus RNA replication in cell culture.

The RNA replication machinery of HCV is a multi-subunit membrane-associated complex. NS5A has emerged as an active component of HCV replicase, possibly involved in regulation of viral replication and resistance to the antiviral effect of interferon. We report here substituted piperazinyl-N-(aryl)benzamides as potent inhibitors of HCV replication exerted via modulation of the dimerization of NS5A.

Tetracyclic indole inhibitors of hepatitis C virus NS5B-polymerase.

We report the evolutionary path from an open-chain series to conformationally constrained tetracyclic indole inhibitors of HCV NS5B-polymerase, where the C2 aromatic is tethered to the indole nitrogen. SAR studies led to the discovery of zwitterionic compounds endowed with good intrinsic enzyme affinity and cell-based potency, as well as superior DMPK profiles to their acyclic counterparts, and ultimately to the identification of a pre-clinical candidate with an excellent predicted human pharmacokinetic profile.

Development of carboxylic acid replacements in indole-N-acetamide inhibitors of hepatitis C virus NS5B polymerase.

Allosteric inhibition of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase enzyme has recently emerged as a viable strategy toward blocking replication of viral RNA in cell-based systems. We report here 2 series of indole-N-acetamides, bearing physicochemically diverse carboxylic acid replacements, which show potent affinity for the NS5B enzyme with reduced potential for formation of glucuronide conjugates. Preliminary optimization of these series furnished compounds that are potent in the blockade of subgenomic HCV RNA replication in HUH-7 cells.

Identification of thieno[3,2-b]pyrroles as allosteric inhibitors of hepatitis C virus NS5B polymerase.

Thieno[3,2-b]pyrroles are a novel class of allosteric inhibitors of HCV NS5B RNA-dependent RNA polymerase which show potent affinity for the NS5B enzyme. Introduction of a polar substituent in the position N1 led to a compound that efficiently blocks subgenomic HCV RNA replication in HUH-7 cells with an EC50 of 2.9 microM.

2-(2-Thienyl)-5,6-dihydroxy-4-carboxypyrimidines as inhibitors of the hepatitis C virus NS5B polymerase: discovery, SAR, modeling, and mutagenesis.

Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed dihydroxypyrimidine carboxylates 2 as novel, reversible inhibitors of the HCV NS5B polymerase.

The design and enzyme-bound crystal structure of indoline based peptidomimetic inhibitors of hepatitis C virus NS3 protease.

The design of a series of peptidomimetic inhibitors of the hepatitis C virus NS3 protease is described. These inhibitors feature an indoline-2-carboxamide as a novel heterocyclic replacement for the P3 amino acid residue and N-terminal capping group of tripeptide based inhibitors. The crystal structure of the ternary NS3/NS4A/inhibitor complex for the most active molecule in this series highlights its suitability as an N-terminal capping group of a dipeptide inhibitor of the NS3 protease.

Evolution, synthesis and SAR of tripeptide alpha-ketoacid inhibitors of the hepatitis C virus NS3/NS4A serine protease.

N-terminal truncation of the hexapeptide ketoacid 1 gave rise to potent tripeptide inhibitors of the hepatitis C virus NS3 protease/NS4A cofactor complex. Optimization of these tripeptides led to ketoacid 30 with an IC50 of 0.38 microM.