Vijayaratnam Santhakumar

Discovery of P2X3 selective antagonists for the treatment of chronic pain

Purinergic receptor P2X3 has been linked to analgesia in a number of pre-clinical models of pain, and is expressed in the human pain perception pathway. Only few P2X3-selective antagonists have been reported to date. This Letter describes the SAR and in vivo analgesic profile of a novel scaffold of selective P2X3 antagonists.

Development of 2,4-diaminopyrimidine derivatives as novel SNSR4 antagonists

2,4-Diaminopyrimidines derivatives were developed as a novel class of SNSR4 antagonists. Structure activity relationship of the diamino pyrimidine core was explored and a tool compound suitable for target validation was identified.

Broad analgesic activity of a novel, selective M1 agonist

&NA; Although the muscarinic receptor family has long been a source of potentially compelling targets for small molecule drug discovery, it was difficult to achieve agonist selectivity within the family. A new class of M1 muscarinic agonists has emerged, and these compounds have been characterized as agonists that activate the receptor at an allosteric site. Members of this class of M1 agonists have been shown to be selective across the muscarinic receptors. However, upon introduction of a novel pharmacologic mechanism, it is prudent to ensure that no new off‐target activities have arisen, particularly within the context of in vivo experiments. Reported here, is the in vitro and in vivo characterization of a novel M1 agonist tool compound, PPBI, and demonstrations that the primary biological effects of PPBI are mediated through M1. PPBI reverses D‐amphetamine locomotor activity, but fails to do so in transgenic mice that do not express M1. PPBI also reverses a natural deficit in a rat cognition model at a level of exposure which also activates cortical circuitry. Most notably, PPBI is analgesic in a variety of rat and mouse models and the analgesic effect of PPBI is reversed by an M1‐preferring antagonist and an M1‐selective toxin. Finally, the pharmacokinetic/pharmacodynamic measures of PPBI are compared across multiple endpoints which highlights that activity in models of psychosis and pain require higher exposures than that required in the cognition model. HighlightsA novel M1 agonist, PPBI is introduced and characterized.The role of cortical M1 receptors in analgesia is exemplified.The PK requirements for PPBI are compared across analgesia, cognition and reversal of hyperdopaminergic activity.

Aminolysis of 3-Phenyl Propylthiol Esters Leading to Diverse Sets of Amides

Abstract 3-Phenyl propylthiol esters were investigated as “activatable” solution phase linkers. These linkers can be activated with silver salts and upon treatment with amines can be converted to the corresponding amides. Under unactivated conditions, the linker is stable to a variety of reagents and reaction conditions including treatment with amines.