Design, synthesis, and evaluation of tetrasubstituted pyridines as potent 5-HT2CReceptor 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 tetra-substituted pyridine core template is outlined, including rationale to account for the unexpected formation of aminopyridine 13 resulting from an ammonia cascade cyclisation. Serotonin (5-hydroxytryptamine, 5-HT 1) acts as a neurotransmitter agonist of at least 14 different receptors classified into seven major families, 5-HT1-7. The 5-HT2 class of GPCR receptors comprises three members 5-HT2A, 5-HT2B and 5-HT2C. Agonism of 5-HT2C in the CNS has been recognised to have potential for the treatment of obesity, urinary incontinence, psychiatric disorders and sexual dysfunction. However, it has been established that selectivity over agonism of structurally related receptors 5HT2A and 5-HT2B is required. Poorly selective agonists have been linked to clinical adverse events in humans. These include hallucinations and cardiovascular effects due to 5-HT2A agonism 2-3 and chronic cardiac valvulopathy and pulmonary hypertension caused by 5-HT2B agonism. Notably the anti-obesity treatment Fen-Phen was withdrawn in 1997 for causing irreversible valvulopathy which has been attributed to chronic 5-HT2B agonism. The resulting search for selective 5-HT2C agonists identified vabicaserin (2) (SCA-136) as a potential therapy for schizophrenia and lorcaserin (3) (APD-356) which was approved in 2012 as Belviq® for treatment of obesity (Figure 1). Numerous other preclinical 5-HT2C agonists have also been reported. Figure 1. Selected 5-HT2C agonists. Previously Pfizer disclosed several 5-HT2C agonist series, 914 including a pyrimidine-fused azepine template that led to the discovery of PF-03246799 (4) which offered good levels of in vitro and in vivo potency. However compound 4, despite offering excellent selectivity over both 5HT2A still showed weak but measurable agonism of 5-HT2B at 10 M in both recombinant cell systems and native human tissue. It was later discovered that 4methylamino substitution 5 could offer an enhancement to 5-HT2C agonist potency and simultaneously offer superior selectivity over 5-HT2B. 13 However, these structural changes rendered amino-substituted pyrimidine compound 5 a substrate for multidrug resistance Pglycoprotein (P-gp), identified by a large efflux ratio (ER=10) as measured using an in vitro transfected MDCK cell line (Figure 2). A previous correlation analysis of all compounds tested in this MDCK-MDR1 assay concluded that compounds with efflux ratios of <2.5 are unlikely to be significantly effluxed from the CNS by P-gp whereas compounds with ratios >3.0 are at significant risk of exhibiting appreciable CNS impairment. In line with this result, preclinical in vivo efficacy studies of compound 5 showed prohibitive levels of CNS restriction limiting therapeutic efficacy even at high plasma concentrations.