Carolyn Diane Dzierba

Chapter 1 Recent Advances in Corticotropin-Releasing Factor Receptor Antagonists

Publisher Summary Corticotropin releasing factor (CRF), a 41 amino acid peptide is considered to be one of the principal regulators of the hypothalamic–pituitary–adrenal (HPA) axis, which coordinates the endocrine, behavioral, and autonomic responses to stress. CRF mediates its action through binding to two well-characterized, class B subtype G-protein coupled receptors, CRF-R1 and CRF-R2. CRF-R1 has been the most extensively studied CRF receptor as a potential therapeutic target, with both preclinical and clinical studies suggesting that antagonists of CRF-R1 may offer promise in treatment of stress-related disorders. This chapter covers advances in the discovery and development of CRF-R1 antagonists. The classes of CRF-R1 antagonists have some key features: (1) an aromatic heterocyclic core that includes an sp2 nitrogen acting as a hydrogen bond acceptor; (2) an aryl ring in an orthogonal orientation to the core ring, which is minimally substituted in the ortho- and para-positions; (3) a halide or small alkyl group ortho to the sp2 nitrogen of the heterocyclic core; and (4) a branched, lipophilic group, with limited tolerance for polar functional groups, para to the sp2 nitrogen of the heterocyclic core. Many potent, small molecule CRF-R1 antagonists from a variety of chemical classes have been reported since the disclosure of CRF-R1 antagonist CP-154,526.

Development of New Benzenesulfonamides As Potent and Selective Nav1.7 Inhibitors for the Treatment of Pain

By taking advantage of certain features in piperidine 4, we developed a novel series of cyclohexylamine- and piperidine-based benzenesulfonamides as potent and selective Nav1.7 inhibitors. However, compound 24, one of the early analogs, failed to reduce phase 2 flinching in the mouse formalin test even at a dose of 100 mpk PO due to insufficient dorsal root ganglion (DRG) exposure attributed to poor membrane permeability. Two analogs with improved membrane permeability showed much increased DRG concentrations at doses of 30 mpk PO, but, confoundingly, only one of these was effective in the formalin test. More data are needed to understand the disconnect between efficacy and exposure relationships.

In vitro Characterization of a small molecule inhibitor of the alanine serine cysteine transporter -1 (SLC7A10).

NMDA receptor hypofunction is hypothesized to contribute to cognitive deficits associated with schizophrenia. Since direct activation of NMDA receptors is associated with serious adverse effects, modulation of the NMDA co‐agonists, glycine or D‐serine, represents a viable alternative therapeutic approach. Indeed, clinical trials with glycine and D‐serine have shown positive results, although concerns over toxicity related to the high‐doses required for efficacy remain. Synaptic concentrations of D‐serine and glycine are regulated by the amino acid transporter alanine serine cysteine transporter‐1 (asc‐1). Inhibition of asc‐1 would increase synaptic D‐serine and possibly glycine, eliminating the need for high‐dose systemic D‐serine or glycine treatment. In this manuscript, we characterize Compound 1 (BMS‐466442), the first known small molecule inhibitor of asc‐1. Compound 1 selectively inhibited asc‐1 mediated D‐serine uptake with nanomolar potency in multiple cellular systems. Moreover, Compound 1 inhibited asc‐1 but was not a competitive substrate for this transporter. Compound 1 is the first reported selective inhibitor of the asc‐1 transporter and may provide a new path for the development of asc‐1 inhibitors for the treatment of schizophrenia.

Design, synthesis, and evaluation of phenylglycinols and phenyl amines as agonists of GPR88.

Small molecule modulators of GPR88 activity (agonists, antagonists, or modulators) are of interest as potential agents for the treatment of a variety of psychiatric disorders including schizophrenia. A series of phenylglycinol and phenylamine analogs have been prepared and evaluated for their GPR88 agonist activity and pharmacokinetic (PK) properties.

The discovery of potent agonists for GPR88, an orphan GPCR, for the potential treatment of CNS disorders

Modulating GPR88 activity is suggested to have therapeutic utility in the treatment of CNS disorders, such as schizophrenia. This Letter will describe the discovery and SAR development of a class of potent GPR88 agonists.

Synthesis and structure-activity relationships of pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones as corticotropin-releasing factor-1 receptor antagonists.

Pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones were evaluated as corticotropin-releasing factor-1 receptor antagonists. The synthesis, SAR studies and pharmacokinetic evaluation of these analogs are described herein.

Discovery of non-zwitterionic aryl sulfonamides as Nav1.7 inhibitors with efficacy in preclinical behavioral models and translational measures of nociceptive neuron activation

Since zwitterionic benzenesulfonamide Nav1.7 inhibitors suffer from poor membrane permeability, we sought to eliminate this characteristic by replacing the basic moiety with non-basic bicyclic acetals and monocyclic ethers. These efforts led to the discovery of the non-zwitterionic aryl sulfonamide 49 as a selective Nav1.7 inhibitor with improved membrane permeability. Despite its moderate cellular activity, 49 exhibited robust efficacy in mouse models of neuropathic and inflammatory pain and modulated translational electromyogram measures associated with activation of nociceptive neurons.

Discovery of morpholine-based aryl sulfonamides as Na v 1.7 inhibitors

Replacement of the piperidine ring in the lead benzenesulfonamide Nav1.7 inhibitor 1 with a weakly basic morpholine core resulted in a significant reduction in Nav1.7 inhibitory activity, but the activity was restored by shortening the linkage from methyleneoxy to oxygen. These efforts led to a series of morpholine-based aryl sulfonamides as isoform-selective Nav1.7 inhibitors. This report describes the synthesis and SAR of these analogs.

[ 3 H]BMT-046091 a potent and selective radioligand to determine AAK1 distribution and target engagement

ABSTRACT Adaptor‐associated kinase 1 (AAK1), a member of the Ark1/Prk1 family of serine/threonine kinases, plays a role in modulating clatherin coated endocytosis of specific surface receptors. We have demonstrated that AAK1 inhibitors are efficacious in rodent models of neuropathic pain (Kostich et al., 2016). Here we have characterized the binding properties and distribution pattern of the tritiated AAK1 radioligand, [3H]BMT‐046091, in rodents and cynomolgus monkeys, and used the radioligand to measure the brain target occupancy following systemic administration of AAK1 inhibitors. We have found that [3H]BMT‐046091 is potent and selective AAK1 inhibitor. It inhibits AAK1 phosphorylation of a peptide derived from a physiologic substrate, the &mgr;2 subunit of the adaptor protein complex, with an IC50 value of 2.8 nM, and is inactive at >5 &mgr;M in a panel of functional or binding assays for receptors, transporters and enzymes. [3H]BMT‐046091 binding in the brain is absent in the AAK1 knockout mouse, and is displaceable with a high concentration of AAK1 inhibitors in wild type mice. Specific [3H]BMT‐046091 binding is widespread in the brain and spinal cord with the highest density in the cortex, hippocampus, amygdala, striatum and thalamus. In the spinal cord, [3H]BMT‐046091 binding appears enriched in the dorsal horn superficial layers. Oral administration of LP‐935509, an AAK1 inhibitor, results in a dose‐dependent occupation of AAK1 binding sites in the brain and spinal cord. The increase in AAK1 binding site occupancy by LP‐935509 correlates with the decrease in antinociceptive responses in the rat chronic constriction injury model of neuropathic pain. HIGHLIGHTS[3H]BMT‐046091 is a potent and selective inhibitor radioligand of AAK1.AAK1 binding sites are widespread in the CNS, and, in the spinal cord, most abundant in the dorsal horn.Ex vivo [3H]BMT‐046091 binding autoradiography is successfully used to measure target engagement of AAK1 inhibitors.LP‐935509, an AAK1 inhibitor, occupies AAK1 binding sites, and the occupancy correlates with anti‐neuropathic pain effects.