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Significance Glucagon-like peptide-1 receptor agonists have become established as a leading class of diabetes medications. However, these peptide-based drugs are administered by subcutaneous injection or, in one case, by a complex oral dosing regimen. We now report the discovery of LY3502970, a potent and selective small-molecule GLP-1R agonist. LY3502970 exhibits preclinical pharmacology equivalent to a marketed injectable GLP-1R agonist and possesses pharmacokinetic properties compatible with oral dosing in humans. Cryoelectron microscopy (cryo-EM) studies reveal an ECD-driven receptor binding mode for LY3502970 that provides a favorable pharmacological profile., Glucagon-like peptide-1 receptor (GLP-1R) agonists are efficacious antidiabetic medications that work by enhancing glucose-dependent insulin secretion and improving energy balance. Currently approved GLP-1R agonists are peptide based, and it has proven difficult to obtain small-molecule activators possessing optimal pharmaceutical properties. We report the discovery and mechanism of action of LY3502970 (OWL833), a nonpeptide GLP-1R agonist. LY3502970 is a partial agonist, biased toward G protein activation over β-arrestin recruitment at the GLP-1R. The molecule is highly potent and selective against other class B G protein–coupled receptors (GPCRs) with a pharmacokinetic profile favorable for oral administration. A high-resolution structure of LY3502970 in complex with active-state GLP-1R revealed a unique binding pocket in the upper helical bundle where the compound is bound by the extracellular domain (ECD), extracellular loop 2, and transmembrane helices 1, 2, 3, and 7. This mechanism creates a distinct receptor conformation that may explain the partial agonism and biased signaling of the compound. Further, interaction between LY3502970 and the primate-specific Trp33 of the ECD informs species selective activity for the molecule. In efficacy studies, oral administration of LY3502970 resulted in glucose lowering in humanized GLP-1R transgenic mice and insulinotropic and hypophagic effects in nonhuman primates, demonstrating an effect size in both models comparable to injectable exenatide. Together, this work determined the molecular basis for the activity of an oral agent being developed for the treatment of type 2 diabetes mellitus, offering insights into the activation of class B GPCRs by nonpeptide ligands.

Activation of glucagon-like peptide-1 receptors (GLP-1R) is a promising approach for the treatment of type 2 diabetes mellitus (T2D), and several peptide analogues of GLP-1 have been successfully developed. Here we identified a new orally active non-peptide GLP-1R agonist, OWL833, and examined its efficacy in cynomolgus monkeys. The agonistic activity of OWL833 was evaluated by measuring cAMP accumulation in cells expressing mammal GLP-1Rs and other glucagon family receptors. In the cells expressing human or cynomolgus monkey GLP-1R, OWL833 promoted cAMP accumulation to the same level achieved by GLP-1, and its EC50 values for human and cynomolgus monkey GLP-1Rs were the same at 1.1 nmol/L. In contrast, OWL833 showed no stimulatory activity on human glucagon, GIP, and GLP-2 receptors. The predicted bioavailability and T1/2 of OWL833 in human based on rodent and non-rodent experimental data are 30% and ∼18 hour, respectively. After OWL833 followed by glucose was intravenously injected in cynomolgus monkeys, OWL833 decreased the blood glucose level via insulin secretion to the same extent as effective concentrations of exenatide, a GLP-1 peptide mimetic, in clinic. Doses of 0.and 0.1 mg/kg OWL833 given orally to cynomolgus monkeys reduced their food intake by 25% and 45%, respectively, as compared with vehicle group, and the effect on food intake was equal to that of 0.3 and 0.6 µg/kg subcutaneous injections of exenatide. No critical finding was observed in the subchronic toxicity studies in rats and cynomolgus monkeys. These findings demonstrate that OWL833 has full agonistic activity on human and cynomolgus GLP-1R and improves glucose tolerance by stimulating insulin secretion, and that it exhibits an anti-feeding activity similar to exenatide. In conclusion, OWL833 has potential as a once-daily, orally active, non-peptide GLP-1 receptor agonist. Disclosure T. Kawai: Employee; Self; Chugai Pharmaceutical Co., Ltd. F. Tanino: Employee; Self; Chugai Pharmaceutical Co., Ltd. M. Fukazawa: Employee; Self; Chugai Pharmaceutical Co., Ltd. K. Ogawa: Employee; Self; Chugai Pharmaceutical Co., Ltd. S. Nagao: Employee; Self; Chugai Pharmaceutical Co., Ltd. H. Yoshino: Employee; Self; Chugai Pharmaceutical Co., Ltd. S. Komatsu: Employee; Self; Chugai Pharmaceutical Co., Ltd. Y. Suzuki: Employee; Self; Chugai Pharmaceutical Co., Ltd. Y. Kawabe: Employee; Self; Chugai Pharmaceutical Co., Ltd..

Resistance of prostate cancer to castration is currently an unavoidable problem. The major mechanisms underlying such resistance are androgen receptor (AR) overexpression, androgen-independent activation of AR, and AR mutation. To address this problem, we developed an AR pure antagonist, CH5137291, with AR nuclear translocation-inhibiting activity, and compared its activity and characteristics with that of bicalutamide. Cell lines corresponding to the mechanisms of castration resistance were used: LNCaP-BC2 having AR overexpression and LNCaP-CS10 having androgen-independent AR activation. VCaP and LNCaP were used as hormone-sensitive prostate cancer cells. In vitro functional assay clearly showed that CH5137291 inhibited the nuclear translocation of wild-type ARs as well as W741C- and T877A-mutant ARs. In addition, it acted as a pure antagonist on the transcriptional activity of these types of ARs. In contrast, bicalutamide did not inhibit the nuclear translocation of these ARs, and showed a partial/full agonistic effect on the transcriptional activity. CH5137291 inhibited cell growth more strongly than bicalutamide in VCaP and LNCaP cells as well as in LNCaP-BC2 and LNCaP-CS10 cells in vitro. In xenograft models, CH5137291 strongly inhibited the tumor growth of LNCaP, LNCaP-BC2, and LNCaP-CS10, whereas bicalutamide showed a weaker effect in LNCaP and almost no effect in LNCaP-BC2 and LNCaP-CS10 xenografts. Levels of prostate-specific antigen (PSA) in plasma correlated well with the antitumor effect of both agents. CH5137291 inhibited the growth of LNCaP tumors that had become resistant to bicalutamide treatment. A docking model suggested that CH5137291 intensively collided with the M895 residue of helix 12, and therefore strongly inhibited the folding of helix 12, a cause of AR agonist activity, in wild-type and W741C-mutant ARs. In cynomolgus monkeys, the serum concentration of CH5137291 increased dose-dependently and PSA level decreased 80% at 100 mg/kg. CH5137291 is expected to offer a novel therapeutic approach against major types of castration-resistant prostate cancers.

Short-step and scalable transformations from 2,6-dibromopyridine to 6-bromopyridine-2-sulfonamide by means of halogen―metal exchange and subsequent reaction with sulfuryl chloride followed by amidation are established. Application of the method for the synthesis of various pyridine sulfonamides is also described.

BACKGROUND Castration-resistant prostate cancer (CRPC) is still dependent on androgen receptor (AR) signaling. We previously reported that a novel nonsteroidal AR pure antagonist, CH4933468, which is a thiohydantoin derivative with a sulfonamide side chain, provided in vitro proof of concept but did not in vivo. METHODS We developed other derivatives, CH5137291, CH5138514, and CH5166623, and their pharmacological properties were compared with CH4933468 and bicalutamide. Agonist/antagonist activities in AR-mediated transactivation, cell proliferation against LNCaP and LNCaP-BC2, and AR translocation were evaluated. Agonist metabolite was monitored in liver microsomes and in pharmacokinetics experiments. Antitumor activities in CRPC xenograft models were examined using LNCaP-BC2 and VCaP-CRPC. RESULTS All CH compounds completely inhibited AR-mediated transactivation and proliferation of LNCaP and LNCaP-BC2. In contrast bicalutamide showed a partial inhibition of AR-mediated transactivation and a proliferation of LNCaP-BC2. AR translocation to nucleus was inhibited by CH compounds, but stimulated by bicalutamide. In the LNCaP-BC2 xenograft model, however, only CH5137291 showed significant inhibition of plasma PSA level and antitumor activity. The other three CH compounds were metabolized to their core structure which had agonist activity. CH5137291 also exhibited antitumor activity in a VCaP-CRPC xenograft model, but bicalutamide did not. CONCLUSIONS The molecular mechanism of the CH compounds, inhibition of AR translocation, was different from bicalutamide and this action could contribute to AR pure antagonist activity. Agonist metabolite diminished the antitumor activity of AR pure antagonist. CH5137291 exhibited antitumor activity in LNCaP-BC2 and VCaP-CRPC xenograft models, suggesting that the compound has potential for the treatment of CRPC. Prostate 71:1344–1356, 2011. © 2011 Wiley-Liss, Inc.

A series of 5,5-dimethylthiohydantoin derivatives were synthesized and evaluated for androgen receptor pure antagonistic activities for the treatment of castration-resistant prostate cancer. Since CH4933468, which we reported previously, had a problem with agonist metabolites, novel thiohydantoin derivatives were identified by applying two strategies. One was the replacement of the alkylsulfonamide moiety by a phenylsulfonamide to avoid the production of agonist metabolites. The other was the replacement of the phenyl ring with a pyridine ring to improve in vivo potency and reduce hERG affinity. Pharmacological assays indicated that CH5137291 (17b) was a potent AR pure antagonist which did not produce the agonist metabolite. Moreover, CH5137291 completely inhibited in vivo tumor growth of LNCaP-BC2, a castration-resistant prostate cancer model.

A series of 5,5-dimethylthiohydantoin derivatives were synthesized and evaluated for androgen receptor pure antagonistic activities for the treatment of hormone refractory prostate cancer. CH4933468 (32d) with a sulfonamide side chain not only exhibited antagonistic activity with no agonistic activity in the reporter gene assay but also inhibited the growth of bicalutamide-resistant cell lines. This compound also inhibited tumor growth of the LNCaP xenograft in mice dose-dependently.

The use of multihop connection, in which a station in between the mobile station and the base station performs hopping relay of the transmission, in CDMA cellular systems should expand the area coverage and reduce the transmitted power per hop. There is a possibility that interference power may be reduced and that system capacity may be enlarged by this approach. Depending on the method of application, however, the system capacity may be decreased due to the interference during hopping. In this study, a basic investigation of interference reduction by multihop connection is first presented. Then, a procedure for selection of the hop stations with a strong capability for reducing the interference power is proposed. Considering a multicellular environment with a CDMA (code division multiple access) cellular scheme, the characteristics of multihop connections are evaluated by computer simulation, assuming packet access. It is shown that multihop connection has the effect of improving system capacity. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 2, 86(10): 17–24, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjb.10185

The first total synthesis of (+/-)-scopadulin, an aphidicolane diterpene, is described. The core structure (A/B/C/D ring system) was constructed by an initial synthesis of the B/C/D ring system by our reported methods and a subsequent A ring cyclization by intramolecular aldol condensation. A highly stereoselective cyanation of the tetracyclic enone by Et2AlCN gave a trans-fused A/B ring system with a beta-cyanide at C-4. Stereoselective construction of a quaternary carbon at C-4 was achieved by alpha-alkylation of the cyano group and conversion of the sterically hindered cyano group to a methyl group via our novel reaction for conversion of primary aliphatic amines into alcohols. Finally, the total synthesis of (+/-)-scopadulin was accomplished by a highly chemo- and stereoselective methylation at C-16 and modification of the C-4 alpha-functionality. The stereoselectivity observed in the MeTi(O-i-Pr)3-mediated methylation for the generation of a tertiary axial alcohol at C-16 is extremely high.