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

Design of a Chemical Probe for the Bromodomain and Plant Homeodomain Finger-Containing (BRPF) Family of Proteins

The bromodomain and plant homeodomain finger-containing (BRPF) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Here, we describe <b>NI-57</b> (<b>16</b>) as new pan-BRPF chemical probe of the bromodomain (BRD) of the BRPFs. Inhibitor <b>16</b> preferentially bound the BRD of BRPF1 and BRPF2 over BRPF3, whereas binding to BRD9 was weaker. Compound <b>16</b> has excellent selectivity over nonclass IV BRD proteins. Target engagement of BRPF1B and BRPF2 with <b>16</b> was demonstrated in nanoBRET and FRAP assays. The binding of <b>16</b> to BRPF1B was rationalized through an X-ray cocrystal structure determination, which showed a flipped binding orientation when compared to previous structures. We report studies that show <b>16</b> has functional activity in cellular assays by modulation of the phenotype at low micromolar concentrations in both cancer and inflammatory models. Pharmacokinetic data for <b>16</b> was generated in mouse with single dose administration showing favorable oral bioavailabilit

Design of a Biased Potent Small Molecule Inhibitor of the Bromodomain and PHD Finger-Containing (BRPF) Proteins Suitable for Cellular and in Vivo Studies

The BRPF (bromodomain and PHD finger-containing) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Evaluation of the BRPF family as a potential drug target is at an early stage although there is an emerging understanding of a role in acute myeloid leukemia (AML). We report the optimization of fragment hit <b>5b</b> to <b>13-d</b> as a biased, potent inhibitor of the BRD of the BRPFs with excellent selectivity over nonclass IV BRD proteins. Evaluation of <b>13-d</b> in a panel of cancer cell lines showed a selective inhibition of proliferation of a subset of AML lines. Pharmacokinetic studies established that <b>13-d</b> had properties compatible with oral dosing in mouse models of disease (<i>F</i>_po 49%). We propose that <b>NI-42</b> (<b>13-d</b>) is a new chemical probe for the BRPFs suitable for cellular and in vivo studies to explore the fundamental biology of these proteins

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