Naldemedine: Peripherally Acting Opioid Receptor Antagonist for Treating Opioid-induced Adverse Effects.

Opioids are widely used for pain management in moderate-to-severe pain. However, opioids are associated with adverse events, such as constipation and emesis/vomiting. To reduce these undesired effects, a structure-activity relationship study of morphinan derivatives was conducted, and a promising lead compound with inhibitory effects on opioid receptors was obtained. Further improvement in the potency and pharmacokinetic profiles of the lead compound led to the discovery of naldemedine, which showed anti-constipation and anti-emetic effects against these adverse events that were induced by morphine without influencing morphine's analgesic effect. Naldemedine was launched in Japan and the USA in 2017 and in the EU in 2019, for treating opioid-induced constipation.

Discovery of naldemedine: A potent and orally available opioid receptor antagonist for treatment of opioid-induced adverse effects.

Structure-activity relationship studies of several morphinan derivatives were conducted to obtain dual antagonists for µ- and δ-opioid receptors. We discovered peripherally restricted dual antagonists for µ/δ-opioid receptors as a new chemotype with a morphinan scaffold, which are orally available and do not easily pass the blood-brain barrier. As we expected, some of these compounds inhibit opioid-induced constipation and emesis/vomiting with limited potential to interfere the analgesic effects of morphine. Among them, naldemedine was selected as a potential drug candidate.

Discovery of S-444823, a potent CB1/CB2 dual agonist as an antipruritic agent.

The optimization of a series of 3-carbamoyl 2-pyridone derivatives as CB agonists is reported. These efforts resulted in the discovery of 3-(2-(1-(cyclohexylmethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocycloocta[b]pyridine-3-carboxamido)thiazol-4-yl)propanoic acid (21), a potent dual CB1/CB2 agonist without CNS side effects induced by CB1 receptor activation. It exhibited strong inhibition of scratching as a 1.0% acetone solution in the pruritic model.

CB 1/2 dual agonists with 3-carbamoyl 2-pyridone derivatives as antipruritics: reduction of CNS side effects by introducing polar functional groups.

Our lead compound 1 showed high affinity for both CB1 and CB2 receptors, suggesting the possibility of inducing psychoactive side effects through the CB1 receptor in the brain. To solve this issue, polar functional groups were introduced at the 3-position of the pyridone core of compound 1 to find CB1/2 dual agonists such as 17 and 20 which did not show any CNS side effects.

Discovery of S-777469: an orally available CB2 agonist as an antipruritic agent.

The discovery of novel CB2 ligands based on the 3-carbamoyl-2-pyridone derivatives by adjusting the size of side chain at 1-, 5- and 6-position is reported. The structure-activity relationship around this template lead to the identification of S-777469 as a selective CB2 receptor agonist, which exhibited the significant inhibition of scratching induced by Compound 48/80 at 1.0 mg/kg po and 10 mg/kg po (55% and 61%, respectively).

Synthesis and activities of oxidative metabolites of the anti-arthritic drug candidate S-2474.

We have synthesized and characterized some oxidative metabolites of S-2474. In this study, we discovered a novel skeleton, the 2,3-dihydrobenzofuran derivative, which inhibited PGE(2) production at a very low concentration and was effective in the anti-carrageenin footpad edema assay.

[Studies on the new antiarthritic drug candidate S-2474].

Various 1,2-isothiazolidine-1,1-dioxide (gamma-sultam) derivatives containing an antioxidant moiety, 2,6-di-tert-butyl-phenol substituent, were prepared. Some compounds that have a lower alkyl group at the 2-position of the gamma-sultam skeleton showed potent inhibitory effects on both cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LO), as well as production of interleukin-1 (IL-1) in in vitro assays. They also proved to be effective in several animal arthritic models without any ulcerogenic activities. Among these compounds, (E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidence)-2-ethyl-1,2- isothiazolidine-1,1-dioxide (S-2474) was selected as an antiarthritic drug candidate. The structure-activity relationships examined and some pharmacological evaluations are described. Furthermore, we have developed an efficient and E-selective synthesis of S-2474, in which alpha-methoxy-p-quinone methide is used as a key intermediate. alpha-Methoxy-p-quinone methide was revealed to be equivalent to a p-hydroxy-protected benzaldehyde. It reacts smoothly with alpha-sulfonyl carbanion to give 1,6-addition intermediates, which can be further processed to provide S-2474 directly in the presence of a base. This procedure gives S-2474 as an almost single isomer on the benzylidene double bond in excellent yield and thus is a very practical method adaptable to large-scale synthesis. The detailed mechanistic aspects are studied and discussed.

Synthesis and biological activity of various derivatives of a novel class of potent, selective, and orally active prostaglandin D2 receptor antagonists. 1. Bicyclo[2.2.1]heptane derivatives.

Novel prostaglandin D(2) (PGD(2)) receptor antagonists were synthesized as a potential new class of antiallergic agents having a bicyclo[2.2.1]heptane ring system with sulfonamide groups. Some of them exhibit extremely potent antagonism of the PGD(2) receptor in radioligand binding and cAMP formation assays with IC(50) values below 50 nM and much less antagonism of TXA(2) and PGI(2) receptors. These potent PGD(2) receptor antagonists, when given orally, dramatically suppress various allergic inflammatory responses such as increased vascular permeability in allergic rhinitis, conjunctivitis, and asthma models. The excellent pharmacological profiles of PGD(2) receptor antagonists, originally synthesized in our laboratories, are of potentially great clinical significance. This study also provides experimental evidence suggesting that PGD(2) plays an important role in the pathogenesis of allergic diseases.

Synthesis and biological activity of various derivatives of a novel class of potent, selective, and orally active prostaglandin D2 receptor antagonists. 2. 6,6-Dimethylbicyclo[3.1.1]heptane derivatives.

In an earlier paper, we reported that novel prostaglandin D(2) (PGD(2)) receptor antagonists having the bicyclo[2.2.1]heptane ring system as a prostaglandin skeleton were a potent new class of antiallergic agents and suppressed various allergic inflammatory responses such as those observed in conjunctivitis and asthma models. In the present study, we synthesized PGD(2) receptor antagonists having the 6,6-dimethylbicyclo[3.1.1]heptane ring system. These derivatives have the amide moiety, in contrast to those with the bicyclo[2.2.1]heptane ring system, which have the sulfonamide group. The derivatives having the 6,6-dimethylbicyclo[3.1.1]heptane ring also exhibited strong activity in PGD(2) receptor binding and cAMP formation assays. In in vivo assays such as allergic rhinitis, conjunctivitis, and asthma models, these series of derivatives showed excellent pharmacological profiles. In particular, compound 45 also effectively suppressed eosinophil infiltration in allergic rhinitis and asthma models. This compound (45, S-5751) is now being developed as a promising alternative antiallergic drug candidate.

Short synthesis of tert-butyl-hydroxylated 3,5-di-tert-butyl-4-hydroxybenzaldehyde: Synthesis of tert-butyl-hydroxylated S-2474.

We have developed a very short synthesis of tert-butyl-hydroxylated di-tert-butyl-4-hydroxybenzaldehyde in which the HBr-DMSO system is used as an effective oxidant (overall yield of 45% for the entire four-step process from 2-tert-butyl-p-cresol). We also accomplished the synthesis of a major metabolite of the antiarthritic drug candidate S-2474.

Highly E-selective and effective synthesis of antiarthritic drug candidate S-2474 using quinone methide derivatives.

We have developed an efficient and E-selective synthesis of an antiarthritic drug candidate (E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide (S-2474; 1), in which alpha-methoxy-p-quinone methide is used as a key intermediate. alpha-Methoxy-p-quinone methide was revealed to be an equivalent to a p-hydroxy protected benzaldehyde. It reacts smoothly with alpha-sulfonyl carbanion to give 1,6-addition intermediates, which can be further processed to provide S-2474 directly in the presence of a base. This procedure gives S-2474 as an almost single isomer on the benzylidene double bond in excellent yield and thus is a very practical method adaptable to large-scale synthesis. The detailed mechanistic aspects are studied and discussed.

Total Synthesis of Terprenin, a Highly Potent and Novel Immunoglobulin E Antibody Suppressant.

Regioselective halogenations and Suzuki reactions ensure proper linkage of the aromatic rings in two total syntheses of terprenin (1). Both routes make it possible to prepare 1 efficiently and in large quantity.

Total Synthesis of Terprenin, a Novel Immunosuppressive p-Terphenyl Derivative.

We achieved a total synthesis of terprenin, a novel potent immunoglobulin E antibody suppressant which was obtained from the fermentation broth of Aspergillus candidus RF-5672 and has a highly oxygenated p-terphenyl skeleton with a prenyloxy side chain. The key steps relied on the Suzuki reaction to construct the terphenyl skeleton and on regioselective halogenations to selectively combine the aromatic rings. The highly efficient and practical production of this important natural product offers promise for the development of a new type of antiallergic drug.