In a previous communication, our efforts leading from 1 to the identification of spiro [cyclohexanedihydropyrano[3,4-b]indole]-amine 2a 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 2a, toward trans-6′-, which is currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain. KEYWORDS: NOP receptor agonists, MOP receptor agonists, cebranopadol, analgesics R ecent publications indicate that small molecules activating both nociceptin/orphanin FQ peptide (NOP) and mu opioid peptide (MOP) receptors may potentiate opiate analgesia and at the same time display an improved side effects profile. 1,2 We have recently reported the discovery of a series of small molecules, characterized by their high NOP and opioid receptor agonistic activity. 3 This series included uncyclized (e.g., 1) as well as spirocyclic examples (e.g., 2a). The discovery of spirocyclic 2a originated from the respective uncyclized analogues, which were potent NOP and MOP receptor binders but sometimes hampered by only partial agonistic NOP and MOP receptor activity. In particular, the spiroindole derivates sparked our interest due to their structural novelty and favorable in vitro and in vivo properties. The leading spiroether 2a exhibited strong efficacy in preclinical models of acute (ED 50 rat tail-flick: 3.63 nmol/kg i.v.) and neuropathic pain (ED 50 rat spinal nerve ligation: 1.05 nmol/kg i.v.) but was hampered by poor pharmacokinetic (PK) properties in rats with high clearance, large volume of distribution, moderate half-life (Cl = 4.0 L/h·kg; V ss = 7.52 L/kg; t 1/2 = 1.6 h), and a critically very low oral bioavailability (F = 4%).We herein report our efforts to further optimize the spiroindole lead 2a, which eventually led to the discovery of trans-6′-fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-spiro-[cyclohexane-1,1′(3′H)-pyrano [3,4-b]indol]-4-amine (3a, cebranopadol), a novel potent analgesic NOP and opioid receptor agonist, currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain.The structure−activity relationship (SAR) established around the uncyclized scaffolds (e.g., 1) suggested that a broad variety of linkers such as alcohols, ethers, and amines are tolerated, showing high NOP and MOP receptor binding affinities. 3 As a result, we applied this knowledge through analogous structural variations to lead structure 2a (region A, Figure 1). These changes were also combined with a targeted approach to improve the poor PK profile, in particular by addressing metabolically liable regions B and C.With this in mind, the transformation of the oxacyclic spiro moiety into a carba-, aza-, or thio-cyclic moiety was investigated. Advancing from the oxacyclic spiro 2a to the azacyclic moiety 5a led to equally potent NOP and MOP receptor binders, as well as the introduction of the N-methyl subunit 6a. Similarly, pot...

ABSTRACT:We report the discovery of spiro [cyclohexanepyrano[3,4-b]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 1 and tryptophol in an oxa-Pictet−Spengler reaction led to the formation of spiroether 2, representing a novel NOP and opioid peptide receptor agonistic chemotype. This finding initially stems from the systematic derivatization of 1, which resulted in alcohols 3−5, ethers 6 and 7, amines 8−10, 22−24, and 26−28, amides 11 and 25, and urea 12, many with low nanomolar binding affinities at the NOP and mu opioid peptide (MOP) receptors. KEYWORDS: NOP receptor agonist, MOP receptor agonist F or decades, opioid peptide receptors have been targeted for the treatment of pain, and the present day opioids remain the most effective clinically used drugs for the treatment of moderate to severe acute and chronic pain. However, opioids also carry the risk of severe side effects such as respiratory depression, nausea, vomiting, and constipation, and their use may lead to physical dependence and tolerance.1 The nociceptin receptor and its endogenous ligand nociceptin/ orphanin FQ (N/OFQ), a 17-amino acid neuropeptide, have been described almost 20 years ago.2,3 Because of its partial homology to the three opioid peptide receptor subtypes mu opioid peptide (MOP), kappa opioid peptide (KOP), and delta opioid peptide (DOP) and its insensitivity to opioid agonists (e.g., morphine) and antagonists (e.g., naloxone), the receptor was initially termed "opioid-receptor-like 1" (ORL 1). More recently, however, it was renamed after its endogenous ligand to nociceptin/orphanin FQ peptide (NOP) receptor. Despite its structural and functional homology to opioid receptors, the NOP receptor is not an opioid peptide receptor from a pharmacological perspective and, as such, is considered a nonopioid member of the opioid peptide receptor family. 4 NOP and MOP receptor agonists modulate pain and nociception via distinct yet related targets. Addressing both mechanisms may constitute a novel approach for the development of innovative analgesics. Indeed, recent publications indicate that concurrent activation of NOP and MOP receptors may potentiate opiate analgesia and at the same time lead to an improved side effect profile. 5,6 We therefore aimed at identifying highly potent, small molecule NOP and MOP receptor agonists.This endeavor started with a literature-to-lead approach based on cyclohexanone 1, which has previously been reported by Lednicer et al. as representing a novel class of analgesics. 7,8 As a starting point it was clear that, due to its size, compound 1 would lack key interactions within the binding pocket of both the NOP and MOP receptors and therefore would have only minimal receptor binding affinities (K i (NOP) = 1.5 μM; K i (MOP) = 1.7 μM). It was our strategy to utilize 1 as a core and its ketone moiety for functionalization. Thus, fixing the 4-...

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Die Synthese von 3-. 6-und 17-Alkyliden-Steroiden durch Wirrtc-Reaktion wird beschrieben und der sterische Verlauf der Reaktion an Hand der Ergebnisse diskutiert.Unsere Versuche zum Auf bau der Dioxyacetonseitenkette der Nebennierenrindenhormone veranlafiteri uns, die Anwendung der WrrrrG-Reaktion 1) auf dem Gebiet der cyclischen Steroidketone eingehender zu untersuchen.Bereits 1957 wurde die WI-rTrG-Reaktion von F. SONDHEIMER und R. MECHOU-LAM^) zur Synthese einer Reihe von Methylensteroiden angewendet und in der Folgezeit von anderen Arbeitsgruppen zur Darstellung weiterer Methyleiisteroide benutzt W. Auch bei Synthesen in der Vitamin D-Reihe fand die WIrrrG-Reaktion Anwendungl.5).Die Reaktion offenkettiger Steroidketone mit hoheren Triphenylphosphin-alkylenen wurde verschiedentlich beschriebens). Dagegen wurde unseres Wissens nur eine Veroffentlichung bekannt, die die Reaktion cyclischer Steroidketone mit hoheren Triphenylphosphin-alkylenen untersuchts).Der Auf bau von Czl-Steroiden, ausgehend von 17-Keto-androstan-Derivaten mit Hilfe der WrrrIc-Reaktion, erfordert als ersten Schritt die Einfuhrung eineskhyliden-Restes a m C-Atom 17. Deshalb wurde zunachst untersucht, ob das Verfahren fur die Synthese von Methylensteroiden auch auf die Synthese hoherer Alkylidensteroide ubertragbar ist.Setzt man in Analogie zu dem Verfahren von F. SONDHEIMER und R. MECHOULAM~) 5a-Cholestanon-(3) mit Athyliden-, Propyliden-, Isopropyliden-bzw. Butylidentriphenylphosphorandie man aus den entsprechenden Alkyltriphenylphosphonium-Abhangigkeit der Ausbeuten an 3-Alkyliden-5a-cholestanen bei der WIrrtG-Synthese vom verwendeten LBsungsmittel 15 75

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