Toru Esaki

AG-041R, a novel indoline-2-one derivative, induces systemic cartilage hyperplasia in rats.

AG-041R (3R-1-(2,2-diethoxyethyl)-3-((4 methylphenyl)aminocarbonylmethyl)-3-((4-methylphenyl) ureido)-indoline-2-one) is a novel small compound synthesized as a cholecystokinin-2 (CCK(2))/gastrin receptor antagonist. In the course of the development of this compound, we discovered unexpectedly that oral administration of a high dose for 4 weeks markedly induced systemic cartilage hyperplasia. This change was histologically observed in the auricles, the trachea, the marginal region of the femoral condyle, the xiphoid process and intervertebral disks in rats. Daily intraarticular injections of AG-041R into rat knee joints for 3 weeks also caused cartilage hyperplasia in the marginal region of the femoral condyle, but no hyperplasia was observed in any other cartilage. We have confirmed that chondrogenic activity of AG-041R is an intrinsic property of the compound, and is not due to its CCK(2)/gastrin receptor antagonistic actions. These results indicate that AG-041R is a novel stimulator of chondrogenesis, and can be expected to be a potent therapeutic agent for cartilage disorders.

Structure of human factor VIIa/tissue factor in complex with a peptide-mimetic inhibitor: high selectivity against thrombin by introducing two charged groups in P2 and P4.

The crystal structure of human factor VIIa/soluble tissue factor (FVIIa/sTF) in complex with a highly selective peptide-mimetic FVIIa inhibitor which shows 1670-fold selectivity against thrombin inhibition has been solved at 2.6 A resolution. The inhibitor is bound to FVIIa/sTF at the S1, S2 and S3 sites and at the additional S1 subsite. Two charged groups, the amidino group in P2 and the carboxylate group in P4, form ionic interactions with Asp60 and Lys192 of FVIIa, respectively. Structural comparisons between factor VIIa and thrombin show that thrombin has oppositely charged residues, Lys60F and Glu192, in the S2 site and the S1 subsites, respectively. These data suggest that the utilization of the differences of charge distribution in the S2 site and the S1 subsites between FVIIa and thrombin is critical for achieving high selectivity against thrombin inhibition. These results will provide valuable information for the structure-based drug design of specific inhibitors for FVIIa/TF.

Development of a Novel Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist (CH5447240), a Potent and Orally Available Small-Molecule for Treatment of Hypoparathyroidism

During the course of derivatization of HTS hit 4a, we have identified a novel small-molecule hPTHR1 agonist, 1-(3,5-dimethyl-4-(2-((2-((1 R,4 R)-4-methylcyclohexyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)ethyl)phenyl)-1-methylurea (CH5447240, 14l). Compound 14l exhibited a potent in vitro hPTHR1 agonist effect with EC20 of 3.0 μM and EC50 of 12 μM and showed excellent physicochemical properties, such as high solubility in fasted state simulated intestinal fluid and good metabolic stability in human liver microsomes. Importantly, 14l showed 55% oral bioavailability and a significantly elevated serum calcium level in hypocalcemic model rats.