Hideaki Fujii

Design, synthesis, and structure–activity relationship of novel opioid κ-agonists

By focusing on 4,5-epoxymorphinan, a traditional opioid skeleton but a new structure in the opioid kappa-agonist research field, and by rationally applying the message-address concept and accessory site hypothesis, we discovered a new chemical class opioid kappa-agonist, TRK-820 (1). Its development as an antipruritus is now in the final stage. Here, the full scope of its design, synthesis, and structure-activity relationship are described.

The pharmacological profile of δ opioid receptor ligands, (+) and (−) TAN-67 on pain modulation

Abstract We designed the nonpeptidic highly selective δ opioid receptor agonist on the basis of message address concept and the accessory site theory and synthesized (±) TAN-67. In spite of highly potent agonistic activity in in vitro assay, (±) TAN-67 (racemate) afforded a weak antinociceptive effect in the mouse tail-flick test. This result led us to separate (±) TAN-67 to optical pure compounds, (+) and (−) TAN-67. An i.t.-treatment with (−) TAN-67 produced profound antinociceptive effects through specifically acting on δ 1 receptors. Unlike (−) TAN-67, i.t.-administered (+) TAN-67 displayed dose-related nociceptive behaviors such as scratching, biting and licking. The effect of (+) TAN-67 was blocked by i.t.-treatment with NTI (δ receptor antagonist) and (−) TAN-67 (δ 1 receptor agonist), but not by morphine (μ receptor agonist). The mechanisms involved in spinal pain modulation induced by (+) and (−) TAN-67 were also described.

Synthesis of a novel 6,14-epoxymorphinan derivative and its pharmacology

A novel 6,14-epoxymorphinan benzamide derivative (NS22) was synthesized, which showed opioid kappa receptor agonistic activity in the [(35)S]GTPgammaS binding assay. The antinociceptive effect of NS22 was evaluated in the tail-flick and the hot-plate test. This compound showed a potent antinociceptive activity in mice by s.c. administration, which was attenuated with nor-BNI (selective opioid kappa receptor antagonist).

Synthesis of a Stable Iminium Salt and Propellane Derivatives

The treatment of morphinan 1 with NaH and MsCl provided very stable iminium salt 7 possessing propellane skeleton. One of the synthesized iminium salts 7, isobutyl derivative 7b, was crystallized and its structure was determined by X-ray crystallography. The natural bond orbital analysis suggested that the stability of the iminium should result from the stereoelectronic effect (hyperconjugation) attributed to their own structures.

(3R)-3-amino-4-(2,4,5-trifluorophenyl)-N-{4-[6-(2-methoxyethoxy)benzothiazol-2-yl]tetrahydropyran-4-yl}butanamide as a potent dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.

Novel series of 3-amino-N-(4-aryl-1,1-dioxothian-4-yl)butanamides and 3-amino-N-(4-aryltetrahydropyran-4-yl)butanamides were synthesized and evaluated as dipeptidyl peptidase IV (DPP-IV) inhibitors. Derivatives incorporating the 6-substituted benzothiazole group showed highly potent DPP-IV inhibitory activity. Oral administration of (3R)-3-amino-4-(2,4,5-trifluorophenyl)-N-{4-[6-(2-methoxyethoxy)benzothiazol-2-yl]tetrahydropyran-4-yl}butanamide (12u) reduced blood glucose excursion in an oral glucose tolerance test.

Structure-Antitussive Activity Relationships of Naltrindole Derivatives. Identification of Novel and Potent Antitussive Agents

We have previously reported antitussive effects of naltrindole (NTI), a typical delta opioid receptor antagonist, in a rat model. The ED50 values of NTI by intraperitoneal and peroral injections were 104 microg/kg and 1840 microg/kg, respectively, comparable to those of codeine. Codeine, one of the most reliable centrally acting antitussive drugs, has micro agonist activity and thus the same side effects as morphine, e.g., constipation, dependency, and respiratory depression. Because NTI is a delta opioid antagonist, its derivatives have potential as highly potent antitussives, free from the mu opioid agonist side effects. We attempted to optimize the NTI derivatives to develop novel antitussive agents. On the basis of the studies of structure-antitussive activity relationships of alkyl substituted NTI derivatives, we designed NTI derivatives with extra ring fused structures. As a clinical candidate, we identified a highly potent new compound, (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5,6-dihydro-3-methoxy-4H-pyrrolo[3,2,1-ij]quinolino[2,1:6,7]morphinan-14-ol (5b) methanesulfonate (TRK-850) which was effective even by oral administration (ED50 6.40 microg/kg).

Design and synthesis of a metabolically stable and potent antitussive agent, a novel δ opioid receptor antagonist, TRK-851

We have previously reported on antitussive effect of (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5,6-dihydro-3-methoxy-4H-pyrrolo[3,2,1-ij]quinolino[2,1:6,7]morphinan-14-ol(1b) methanesulfonate (TRK-850), a selective delta opioid receptor antagonist which markedly reduced the number of coughs in a rat cough model. We designed TRK-850 based on naltrindole (NTI), a typical delta opioid receptor antagonist, to improve its permeability through the blood-brain barrier by introducing hydrophobic moieties to NTI. The ED(50) values of NTI and compound 1b by intraperitoneal injections were 104 microg/kg and 2.07 microg/kg, respectively. This increased antitussive potency probably resulted from the improved brain exposure of compound 1b. However, 1b was extremely unstable toward metabolism by cytochrome P450. In this study, we designed and synthesized compound 1b derivatives to improve the metabolic instability, which resulted in affording highly potent and metabolically stable oral antitussive agent (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolino[2,1:6,7]morphinan-3,14-diol (1c) methanesulfonate (TRK-851).

Syntheses of 4,6′-epoxymorphinan derivatives and their pharmacologies

A modification of the message site in the skeleton of naltrexone was carried out to improve the potency and selectivity of the compound for an opioid receptor subtype. In the course of conversion, we synthesized 7-membered ring ether derivatives, which had an inserted OCH(2) group between 4- and 6-positions of morphinan skeleton. One of the 7-membered ring ether derivatives possessed more potent antagonistic activity than naltrexone for the mu opioid receptor. Another compound possessing 17-methyl group derived from noroxycodone may be a mu opioid receptor partial agonist and showed analgesic activity. We are currently examining the subtype selectivity of these compounds.

Novel series of 3-amino-N-(4-aryl-1,1-dioxothian-4-yl)butanamides as potent and selective dipeptidyl peptidase IV inhibitors.

A series of novel 3-amino-N-(4-aryl-1,1-dioxothian-4-yl)butanamides were investigated as dipeptidyl peptidase IV (DPP-4) inhibitors. Introduction of a 4-phenylthiazol-2-yl group showed highly potent DPP-4 inhibitory activity. Among various derivatives, (3R)-3-amino-N-(4-(4-phenylthiazol-2-yl)-tetrahydro-2H-thiopyran-4-yl)-4-(2,4,5-trifluorophenyl)butanamide 1,1-dioxide (30) reduced blood glucose excursion in an oral glucose tolerance test by oral administration.

Rational Drug Design of δ Opioid Receptor Agonist TAN-67 from δ Opioid Receptor Antagonist NTI

A highly selective nonpeptidic δ opioid receptor agonist TAN-67, (4aS *, 12aR *)-4a-(3-hydroxyphenyl)-2-methyl-1,2,3,4,4a,5,12,12a-octahydropyrido[3,4-b]acridine was designed on the basis of the message-address concept and the accessory site theory. (−)-TAN-67 is a potent and selective δ 1 opioid receptor agonist and shows strong antinociceptive, cardioprotective, and antiarrhythmic effects. By contrast, (+)-TAN-67 induced hyperalgesia, the opposite effect of antinociception. An important intermediate ketone for the TAN-67 synthesis, (4aS *, 8aR *)-4a-(3-methoxyphenyl)-2-methyl-6-oxodecahydroisoquinoline, has two structural features: a trans-fused bicyclic heterocycle and a quaternary carbon stereocenter at the bridgehead position. Syntheses of the intermediate ketone reported by some research groups are described. The synthesis of chiral TNA-67 is also shown.