Quantitative Assessment of Drug Delivery to Tissues and Association with Phospholipidosis: A Case Study with Two Structurally Related Diamines in Development

Drug induced phospholipidosis (PLD) may be observed in the preclinical phase of drug development and pose strategic questions. As lysosomes have a central role in pathogenesis of PLD, assessment of lysosomal concentrations is important for understanding the pharmacokinetic basis of PLD manifestation and forecast of potential clinical appearance. Herein we present a systematic approach to provide insight into tissue-specific PLD by evaluation of unbound intracellular and lysosomal (reflecting acidic organelles) concentrations of two structurally related diprotic amines, GRT1 and GRT2. Their intratissue distribution was assessed using brain and lung slice assays. GRT1 induced PLD both <i>in vitro</i> and <i>in vivo</i>. GRT1 showed a high intracellular accumulation that was more pronounced in the lung, but did not cause cerebral PLD due to its effective efflux at the blood–brain barrier. Compared to GRT1, GRT2 revealed higher interstitial fluid concentrations in lung and brain, but more than 30-fold lower lysosomal trapping capacity. No signs of PLD were seen with GRT2. The different profile of GRT2 relative to GRT1 is due to a structural change resulting in a reduced basicity of one amino group. Hence, by distinct chemical modifications, undesired lysosomal trapping can be separated from desired drug delivery into different organs. In summary, assessment of intracellular unbound concentrations was instrumental in delineating the intercompound and intertissue differences in PLD induction <i>in vivo</i> and could be applied for identification of potential lysosomotropic compounds in drug development

Discovery of Spiro[cyclohexane-dihydropyrano[3,4‑<i>b</i>]indole]-amines as Potent NOP and Opioid Receptor Agonists

We report the discovery of spiro­[cyclohexane-pyrano­[3,4-<i>b</i>]­indole]-amines, as functional nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonists with strong efficacy in preclinical models of acute and neuropathic pain. Utilizing 4-(dimethylamino)-4-phenylcyclo-hexanone <b>1</b> and tryptophol in an oxa-Pictet–Spengler reaction led to the formation of spiroether <b>2</b>, representing a novel NOP and opioid peptide receptor agonistic chemotype. This finding initially stems from the systematic derivatization of <b>1</b>, which resulted in alcohols <b>3</b>–<b>5</b>, ethers <b>6</b> and <b>7</b>, amines <b>8</b>–<b>10</b>, <b>22</b>–<b>24</b>, and <b>26</b>–<b>28</b>, amides <b>11</b> and <b>25</b>, and urea <b>12</b>, many with low nanomolar binding affinities at the NOP and mu opioid peptide (MOP) receptors

Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol

In a previous communication, our efforts leading from <b>1</b> to the identification of spiro­[cyclohexane-dihydropyrano­[3,4-<i>b</i>]­indole]-amine <b>2a</b> as analgesic NOP and opioid receptor agonist were disclosed and their favorable in vitro and in vivo pharmacological properties revealed. We herein report our efforts to further optimize lead <b>2a</b>, toward <i>trans</i>-6′-fluoro-4′,9′-dihydro-<i>N</i>,<i>N</i>-dimethyl-4-phenyl-spiro­[cyclohexane-1,1′(3′<i>H</i>)-pyrano­[3,4-<i>b</i>]­indol]-4-amine (cebranopadol, <b>3a</b>), which is currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain