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.

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. Examples from this novel scaffold were found to be highly potent and fully efficacious agonists of the human CB2 receptor with excellent selectivity against CB1, often having no CB1 agonist activity at the highest concentration measured (>100 µM). Compound 26 is a centrally penetrant molecule which possesses good biopharmaceutical properties, is highly water-soluble, and demonstrates robust oral activity in rodent models of joint pain. In addition, the peripherally restricted molecule 22 also demonstrated significant efficacy in the same analgesic model of rodent inflammatory pain.

Asymmetric synthesis of an N-acylpyrrolidine for inhibition of HCV polymerase.

A practical asymmetric synthesis of a highly substituted N-acylpyrrolidine on multi-kilogram scale is described. The key step in the construction of the three stereocenters is a [3+2] cycloaddition of methyl acrylate and an imino ester prepared from l-leucine t-butyl ester hydrochloride and 2-thiazolecarboxaldehyde. The cycloaddition features novel asymmetric catalysis via a complex of silver acetate and a cinchona alkaloid, particularly hydroquinine, with complete diastereomeric control and up to 87% enantiomeric control. The alkaloid serves as a ligand as well as a base for the formation of the azomethine ylide or 1,3-dipole. Experiments have shown that the hydroxyl group of hydroquinine is a critical element for the enantioselectivities observed. The cycloaddition methodology is also applicable to methylvinyl ketone, providing access to either alpha- or beta-epimers of 4-acetylpyrrolidine depending on the reaction conditions utilized. The synthesis also highlights an efficient N-acylation, selective O- versus N-methylation, and a unique ester reduction with NaBH4-MeOH catalyzed by NaB(OAc)3H that not only achieves excellent chemoselectivity but also avoids formation of the undesired but thermodynamically favored epimer. The highly functionalized target is synthesized in seven linear steps from l-leucine t-butyl ester hydrochloride with all three isolated intermediates being highly crystalline.

Optimization of novel acyl pyrrolidine inhibitors of hepatitis C virus RNA-dependent RNA polymerase leading to a development candidate.

Optimization of a pyrrolidine-based template using structure-based design and physicochemical considerations has provided a development candidate 20b (3082) with submicromolar potency in the HCV replicon and good pharmacokinetic properties.