Cyclic analogues of N-[3,5-bis(trifluoromethyl)benzyl]-7,8-dihydro-N, 7-dimethyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxamide (1) having a 6-9-membered ring (6-9) were synthesized and evaluated for NK(1) antagonistic activities. The 8-membered ring compound with a beta-methyl group at the C((9))-position, (aR,9R)-7-[3, 5-bis(trifluoromethyl)benzyl]-8,9,10, 11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g] [1, 7]naphthyridine-6,13-dione [(aR,9R)-8b], was atropodiastereoselectively synthesized by cyclization of a chiral intermediate, 10g. On the other hand, the 7-membered ring compound with a beta-methyl group at the C((9))-position [(9S)-7b] was obtained as an equilibrium mixture of atropisomers with a ratio of ca. 3:2 in solution at room temperature (measured by NMR in CDCl(3)). Compounds (9S)-7b and (aR,9R)-8b exhibited excellent antagonistic activities both in vitro [IC(50) (inhibition of [(125)I]BH-SP binding in human IM-9 cells) = 0.28 and 0.45 nM, respectively] and in vivo (iv and po). Significantly, the in vitro activity of (aR, 9R)-8b was ca. 750-fold higher than that of its enantiomer (aS, 9S)-8b, ca. 40-fold higher than its atropisomer (aS,9R)-8b, and ca. 20-fold higher than its diastereomer (aR,9S)-8b. The structure-activity relationships in this series, along with the X-ray analysis of (aR,9R)-8b, indicated that the stereochemistry around the -C((6))(=O)-N((7))-CH(2)Ar moiety is important for NK(1) receptor recognition. The NK(1) antagonists showed effects on bladder functions in guinea pigs upon intravenous injection: i.e., the antagonists increased the shutdown time of distension-induced rhythmic bladder contractions and the bladder volume threshold, and the effects on the shutdown time were found to correlate well with the NK(1) antagonistic activities. Compound (aR,9R)-8b has been identified as a potential clinical candidate for the treatment of bladder function disorders.

Irritable bowel syndrome (IBS) is a common disorder mainly characterized by altered bowel habits and visceral pain. In this study, we investigated the role of tachykinin NK 1 receptors in the visceral pain response (abdominal muscle contraction) caused by colorectal distention in rabbits previously subjected to colonic irritation, using the selective tachykinin NK 1 receptor antagonists TAK-637 [(aR,9R)-7-[3,5-Bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-Intracolorectal administration of 0.8% acetic acid solution enhanced the nociceptive response to colorectal distention, producing a significant increase in the number of abdominal muscle contractions. Under these conditions, intraduodenal TAK-637 (0.1-3 mg/kg) dose dependently decreased the number of distention-induced abdominal contractions, and a significant inhibitory effect was observed with doses of 0.3 to 3 mg/kg. Another tachykinin NK 1 antagonist, (Ϯ)-CP-99,994, also reduced the number of abdominal contractions. In contrast, the enantiomer of TAK-637 (which has very weak tachykinin NK 1 receptor antagonistic activity), trimebutine maleate, ondansetron, and atropine sulfate did not inhibit the abdominal response. The main metabolite of TAK-637, which has more potent tachykinin NK 1 receptor antagonistic activity but permeates the central nervous system less well than TAK-637, produced less inhibition of the viscerosensory response. When given intrathecally, TAK-637 and (Ϯ)-CP-99,994 markedly reduced the number of abdominal contractions. These results suggest that tachykinin NK 1 receptors play an important role in mediating visceral pain and that TAK-637 inhibits the viscerosensory response to colorectal distention by antagonizing tachykinin NK 1 receptors, mainly in the spinal cord. They also suggest that TAK-637 may be useful in treating functional bowel disorders such as IBS.

A series of 4-phenylisoquinolone derivatives were synthesized and evaluated for NK1 (substance P) antagonist activity. Highly potent antagonists, 4-phenyl-3-isoquinolone-N-benzylcarboxamides (11), were discovered from the structure-activity relationship studies on the isoquinolone-urea lead 1a. Optimization of the activity in this series resulted in the development of 5-phenyl-6-pyrido[3,4-b]pyridine-N-benzylcarboxamides (30) which are highly potent orally active NK1 antagonists. Among the compounds synthesized, N-[3,5-bis(trifluoromethyl)benzyl]-7,8-dihydro-N,7-dimethyl-8-oxo-5- (substituted phenyl)-6-pyrido[3,4-b]pyridinecarboxamides (30a,f,g) showed excellent antagonist activities with IC50 values (in vitro inhibition of [125I]-BH-SP binding in human IM-9 cells) of 0.21-0.34 nM and ED50 values (in vivo inhibition of capsaicin-induced plasma extravasation in guinea-pig trachea, iv) of 0.017-0.030 mg/kg. These compounds exhibited significantly potent activity upon oral administration with ED50 values of 0.068-0.17 mg/kg. Conformational studies on 30g indicated that the two stable conformers of 30g are quite similar to those of CP-99,994.

A potent and orally active NK1 antagonist, trans-N-[3, 5-bis(trifluoromethyl)benzyl]-7,8-dihydro-N, 7-dimethyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxamide (1t), was shown to exist as a mixture of separable and stable (R)- and (S)-atropisomers (1t-A and 1t-B) originating from the restricted rotation around the -C(6)-C(=O)- bond; the antagonistic activities of 1t-A were ca. 6-13-fold higher than those of 1t-B. Analogues of 1t (3), which have (S)- and (R)-methyl groups at the benzylic methylene portion of 1t, were prepared and separated into the diastereomeric atropisomers, 3a-A, 3a-B and 3b-A, 3b-B, in enantiomerically pure forms. Among the four isomers of 3, the (aR, S)-enantiomer (3a-A) exhibited the most potent antagonistic activities with an IC50 value of 0.80 nM (in vitro inhibition of [125I]BH-SP binding in human IM-9 cells) and ED50 values of 9.3 micrograms/kg (iv) and 67.7 micrograms/kg (po) (in vivo inhibition of capsaicin-induced plasma extravasation in guinea pig trachea), while the activity of the (aS,R)-enantiomer (3b-B) was the weakest with an IC50 value of 620 nM. The structure-activity relationships in this series of antagonists indicate that the (R)-configuration at the axial bond and the stacking (or stacking-like) conformation between the two phenyl rings as shown in 1t-A and 3a-A are essential for high-affinity binding and suggest that the amide moiety functions as a hydrogen bond acceptor in the interaction with the receptor.

IkB kinase (IKK) has been identified as a serine-threonine kinase complex, which phosphorylates the inhibitor of NFkB (IkB). [1][2][3] This complex is composed of three subunits, i.e. the catalytic subunits IKKa and IKKb, and the regulatory subunit IKKg, also called IKK-1, IKK-2, and NEMO, respectively. The complex plays a critical role in a signaling pathway leading to NF-kB (nuclear factor-kB) activation. 4) The activation of IKK by cytokine signals (tumor necrosis factor (TNF)-a, interleukin (IL)-1 etc.), lipopolysaccharide (LPS), and stress leads to phosphorylation of IkB, which triggers poly-ubiquitinylation and proteasome-dependent degradation of IkB, resulting in transcriptional activation of NF-kB. It has been recognized that the kinase IKKb plays a major role in activation of NF-kB via classical (canonical) pathway, and activation of the classical pathway promotes the production of TNF-a, IL-1, intercellular adhesion molecule (ICAM)-1, and cyclooxygenase (COX)-2, which indicates that this pathway is important for inflammation and the innate immune system. Therefore, IKKb inhibitors are expected to be useful for the treatment of acute and chronic inflammatory diseases and autoimmune disorders, such as rheumatoid arthritis (RA). 5) Alternatively, IKKb inhibitors are also thought to be useful for the treatment of type 2 diabetes because activation or overexpression of the IKKb attenuated insulin signaling.6) In addition, IKKb inhibitors may also have application for the treatment of asthma, chronic obstructive pulmonary disease (COPD), 7) and cancer. 8) Because of the key role played by the IKK complex in the NF-kB mediated transcription, and of the druggability of kinases as a target class, numerous companies have been pursuing discovery programs aimed at identifying small molecule inhibitors of this enzyme. 9,10) As part of our program to discover new IKK inhibitors, we identified 1 (MAYBRIDGE) as a potent hit compound. However, AstraZeneca has previously reported that the structurally-analogous urea derivative 2, 11) which could be derived from the compound 1, exhibited excellent inhibitory activity. The introduction of a urea group resulted in the improvement of activity by as much as 100-fold compared with the amino derivative 1 (Fig. 1). Because the benzene ring of 2 was considered to be coplanar to the thiophene ring in it's active conformation, 11) it seemed that the relative orientation of the urea, carbamoyl, and benzene was important for IKKb inhibition. Thus, it was also thought that constraining the terminal benzene to be in the active conformation could improve activity. From this point of view and taking into consideration of patentability issues, we designed tricyclic fused furan derivatives for the development of novel IKK inhibitors. In this manuscript, we describe the synthesis and the SAR of the series of tricyclic furan derivatives. ChemistryThe synthesis of benzothieno[3,2-b]furans 13a-i and 16a-o having a 2-carbamoyl and 3-urea group, is outlined in Chart 1. The substituted thiopheno...