Rotationally constrained 2,4-diamino-5,6-disubstituted pyrimidines: a new class of histamine H4 receptor antagonists with improved druglikeness and in vivo efficacy in pain and inflammation models

A new structural class of histamine H 4 receptor antagonists (6-14) was designed based on rotationally restricted 2,4-diaminopyrimidines. Series compounds showed potent and selective in vitro H 4 antagonism across multiple species, good CNS penetration, improved PK properties compared to reference H 4 antagonists, functional H 4 antagonism in cellular and in vivo pharmacological assays, and in vivo anti-inflammatory and antinociceptive efficacy. One compound, 10 (A-943931), combined the best features of the series in a single molecule and is an excellent tool compound to probe H 4 pharmacology. It is a potent H 4 antagonist in functional assays across species (FLIPR Ca (2+) flux, K b < 5.7 nM), has high (>190x) selectivity for H 4, and combines good PK in rats and mice (t 1/2 of 2.6 and 1.6 h, oral bioavailability of 37% and 90%) with anti-inflammatory activity (ED 50 = 37 micromol/kg, mouse) and efficacy in pain models (thermal hyperalgesia, ED 50 = 72 micromol/kg, rat).     

Safe Introduction of Ancillary Trocars

The problem of laparoscopic entry is currently still unsolved, and despite the various techniques adopted by the surgical community, it has not yet been determined which is the correct access in all patients. Add to this the problem of safe ancillary port introduction; all surgeons must avoid vascular and visceral damage. The 2 most common problems with second port trocars are inferior and superior epigastric artery damage, and bowel loops and adhesions. Over the years, we have developed 2 steps that are very useful to avoid iatrogenic injuries to vessels and viscera. In this brief report, we explain the following 2 simple steps, called by the authors “yellow island” port entry and second trocar “tip entry guided” by a suction cannula. In our practice of more than 3400 conventional laparoscopies, with data from patients with different characteristics, surgeons who have introduced laparoscopic surgery into their daily practice might teach these steps to young fellows and trainees.