Design, Synthesis, and Evaluation of Tetrasubstituted Pyridines as Potent 5-HT2C Receptor Agonists.

A series of pyrido[3,4-d]azepines that are potent and selective 5-HT2C receptor agonists is disclosed. Compound 7 (PF-04781340) is identified as a suitable lead owing to good 5-HT2C potency, selectivity over 5-HT2B agonism, and in vitro ADME properties commensurate with an orally available and CNS penetrant profile. The synthesis of a novel bicyclic tetrasubstituted pyridine core template is outlined, including rationale to account for the unexpected formation of aminopyridine 13 resulting from an ammonia cascade cyclization.We would like to thank the EPSRC (SVL, grant nº EP/K0099494/1 and nº EP/K039520/1) for financial support.This is the accepted manuscript. The final version is available from ACS at http://pubs.acs.org/doi/abs/10.1021/ml500507v

Design, Synthesis, and Evaluation of Tetrasubstituted Pyridines as Potent 5‑HT_2C Receptor Agonists

A series of pyrido­[3,4-<i>d</i>]­azepines that are potent and selective 5-HT_2C receptor agonists is disclosed. Compound <b>7</b> (PF-04781340) is identified as a suitable lead owing to good 5-HT_2C potency, selectivity over 5-HT_2B agonism, and <i>in vitro</i> ADME properties commensurate with an orally available and CNS penetrant profile. The synthesis of a novel bicyclic tetrasubstituted pyridine core template is outlined, including rationale to account for the unexpected formation of aminopyridine <b>13</b> resulting from an ammonia cascade cyclization

Multiparameter Optimization in CNS Drug Discovery: Design of Pyrimido[4,5‑<i>d</i>]azepines as Potent 5‑Hydroxytryptamine 2C (5-HT_2C) Receptor Agonists with Exquisite Functional Selectivity over 5‑HT_2A and 5‑HT_2B Receptors

A series of 4-substituted pyrimido­[4,5-<i>d</i>]­azepines that are potent, selective 5-HT_2C receptor partial agonists is described. A rational medicinal chemistry design strategy to deliver CNS penetration coupled with SAR-based optimization of selectivity and agonist potency provided compounds with the desired balance of preclinical properties. Lead compounds <b>17</b> (PF-4479745) and <b>18</b> (PF-4522654) displayed robust pharmacology in a preclinical canine model of stress urinary incontinence (SUI) and no measurable functional agonism at the key selectivity targets 5-HT_2A and 5-HT_2B in relevant tissue-based assay systems. Utilizing recent advances in the structural biology of GPCRs, homology modeling has been carried out to rationalize binding and agonist efficacy of these compounds