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Two new series of monoamine triple reuptake inhibitors (TRIs) have been discovered through scaffold homologation of our recently reported series of 3,3-disubstituted pyrrolidine TRIs. The regioisomeric 2- and 3-ketopyrrolidines demonstrated high levels of potency against all three monoamine transporters as well as good human in vitro stability, low drug–drug interaction potential and a decreased propensity for hERG channel binding. Representative compounds from these series displayed good in vivo pharmacokinetics and high monoamine receptor occupancies which are indicators of good brain penetration.

The purinoceptor subtypes P2X(3) and P2X(2/3) have been shown to play a pivotal role in models of various pain conditions. Identification of a potent and selective dual P2X(3)/P2X(2/3) diaminopyrimidine antagonist RO-4 prompted subsequent optimization of the template. This paper describes the SAR and optimization of the diaminopyrimidine ring and particularly the substitution of the 2-amino group. The discovery of the highly potent and drug-like dual P2X(3)/P2X(2/3) antagonist RO-51 is presented.

A novel approach to 2′-O-alkylpyrimidine nucleosides involving a 3′- hydroxyl assisted intramolecular delivery of a divalent metal alkoxide leads to a regiospecific opening of the anhydropyrimidine linkage at the 2′-position. Thus, reaction of 5′-protected 2,2′-anhydrouridine with magnesium or calcium alkoxides in DMF affords exclusively the corresponding 2′-O-alkyluridines in reasonable yields.

The synthesis of 2′-amino-2′-deoxypyrimidine 5′-triphosphates is described. The 2′-amino-2′-deoxyuridine 5′-triphosphate is obtained from uridine in four steps with 25% overall yield. The 2′-amino-2′-deoxycytidine 5′-triphosphate is obtained from uridine in seven steps with 13% overall yield.

A high yield process for the conversion of 2,2′-cyclouridine to 2′-azido-2′-deoxyuridine was developed. The procedure utilizes a lithium azide:TMEDA complex generated in situ from the reaction of lithium fluoride and azidotrimethylsilane in DMF with TMEDA added as a co-solvent.

The synthesis of 2′-amino-2′-deoxypyrimidine 5′-triphosphates is described. The 2′-amino-2′-deoxyuridine 5′-triphosphate is obtained from uridine in four steps with 25% overall yield. The 2′-amino-2′-deoxycytidine 5′-triphosphate is obtained from uridine in seven steps with 13% overall yield.

A novel approach to 2′-O-alkylpyrimidine nucleosides involving a 3′- hydroxyl assisted intramolecular delivery of a divalent metal alkoxide leads to a regiospecific opening of the anhydropyrimidine linkage at the 2′-position. Thus, reaction of 5′-protected 2,2′-anhydrouridine with magnesium or calcium alkoxides in DMF affords exclusively the corresponding 2′-O-alkyluridines in reasonable yields.

Despite the extensive literature describing the role of the ATP-gated P2X 3 receptors in a variety of physiological processes the potential of antagonists as therapeutic agents has been limited by the lack of drug-like selective molecules. In this paper we report the discovery and optimization of RO-85, a novel drug-like, potent and selective P2X 3 antagonist. High-throughput screening of the Roche compound collection identified a small hit series of heterocyclic amides from a large parallel synthesis library. Rapid optimization, facilitated by high-throughput synthesis, focusing on increasing potency and improving drug-likeness resulted in the discovery of RO-85.

P2X purinoceptors are ligand-gated ion channels whose endogenous ligand is ATP. Both the P2X(3) and P2X(2/3) receptor subtypes have been shown to play an important role in the regulation of sensory function and dual P2X(3)/P2X(2/3) antagonists offer significant potential for the treatment of pain. A high-throughput screen of the Roche compound collection resulted in the identification of a novel series of diaminopyrimidines; subsequent optimization resulted in the discovery of RO-4, a potent, selective and drug-like dual P2X(3)/P2X(2/3) antagonist.

A series of 3,3-disubstituted pyrrolidine monoamine triple reuptake inhibitors were discovered. Analogues with low nanomolar potency, good human in vitro microsomal stability and in vitro permeability, and low drug-drug interaction potential are described. One example showed in vivo anti-depressant-like effects in the mouse tail suspension assay with a minimum effective dose of 30 mg/kg i.p.

A high yield process for the conversion of 2,2′-cyclouridine to 2′-azido-2′-deoxyuridine was developed. The procedure utilizes a lithium azide:TMEDA complex generated in situ from the reaction of lithium fluoride and azidotrimethylsilane in DMF with TMEDA added as a co-solvent.