Identification of Novel Potent NSD2-PWWP1 Ligands Using Structure-Based Design and Computational Approaches.

Dysregulation of histone methyl transferase nuclear receptor-binding SET domain 2 (NSD2) has been implicated in several hematological and solid malignancies. NSD2 is a large multidomain protein that carries histone writing and histone reading functions. To date, identifying inhibitors of the enzymatic activity of NSD2 has proven challenging in terms of potency and SET domain selectivity.

The SAR development of substituted purine derivatives as selective CB2 agonists for the treatment of chronic pain.

Osteoarthritis (OA) and the associated joint pain are highly prevalent and a leading cause of disability. We have previously reported the identification of a series of purines as selective CB2 agonists and the identification of compound 1 as a clinical candidate for the treatment of joint pain. In this article we describe the further SAR development of the purine scaffold leading to the discovery of compound 6 as a potent, CNS penetrating CB2 agonist with high selectivity for CB2 over CB1 and oral efficacy in animal models of chronic OA pain.

Unique pharmacology of heteromeric α7β2 nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes.

α7β2 is a novel type of nicotinic acetylcholine receptor shown to be uniquely expressed in cholinergic neurons of the basal forebrain and in hippocampal interneurons. We have compared the pharmacological properties of recombinant homomeric α7 and heteromeric α7β2 nicotinic acetylcholine receptors in order to reveal the pharmacological consequences of β2 subunit incorporation into the pentamer. The non-selective agonist epibatidine did not distinguish α7β2 from α7 nicotinic acetylcholine receptors, but three other non-selective agonists (nicotine, cytisine and varenicline) were less efficacious on α7β2 than on α7.

Selective cannabinoid receptor type 2 (CB2) agonists: optimization of a series of purines leading to the identification of a clinical candidate for the treatment of osteoarthritic pain.

A focused screening strategy identified thienopyrimidine 12 as a cannabinoid receptor type 2 agonist (hCB2) with moderate selectivity over the hCB1 receptor. This initial hit suffered from poor in vitro metabolic stability and high in vivo clearance. Structure-activity relationships describe the optimization and modification to a new more polar series of purine CB2 agonists.

Discovery and optimization of novel purines as potent and selective CB2 agonists.

A focused screening strategy identified thienopyrimidine 1 as a hCB2 cannabinoid receptor agonist with moderate selectivity over the hCB1 receptor. This initial hit suffered from poor in vitro metabolic stability and high in vivo clearance. Structure-activity relationships describe the optimization and modification to a less lipophilic purine core.

Total synthesis of (+/-)-alpha-isosparteine, (+/-)-beta-isosparteine, and (+/-)-sparteine from a common tetraoxobispidine intermediate.

The three title alkaloids were separately prepared in stereocontrolled fashion from a common tetraoxobispidine precursor, 3,7-diallyl-2,4,6,8-tetraoxo-3,7-diazabicyclo[3.3.1]nonane (16).

A practical synthesis of (+/-)-alpha-isosparteine from a tetraoxobispidine core.

[reaction: see text] The title alkaloid was synthesized in racemic form from 3,7-diallyl-2,4,6,8-tetraoxo-3,7-diazabicyclo[3.3.1]nonane (7) by a regioselective diallylation reaction followed by double ring-closing olefin metathesis and exhaustive reduction.