Hiroharu Matsuoka

Discovery of Tofogliflozin, a Novel C-Arylglucoside with an O-Spiroketal Ring System, as a Highly Selective Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

Inhibition of sodium glucose cotransporter 2 (SGLT2) has been proposed as a novel therapeutic approach to treat type 2 diabetes. In our efforts to discover novel inhibitors of SGLT2, we first generated a 3D pharmacophore model based on the superposition of known inhibitors. A search of the Cambridge Structural Database using a series of pharmacophore queries led to the discovery of an O-spiroketal C-arylglucoside scaffold. Subsequent chemical examination combined with computational modeling resulted in the identification of the clinical candidate 16d (CSG452, tofogliflozin), which is currently under phase III clinical trials.

Physicochemical parameters responsible for the affinity of methotrexate analogs for rat canalicular multispecific organic anion transporter (cMOAT/MRP2).

AbstractPurpose. Canalicular multispecific organic anion transporter (cMOAT/MRP2) is known to exhibit a broad substrate specificity toward amphiphatic organic anions, including methotrexate (MTX). The present study aims to identify the physicochemical properties of MTX derivatives that correlate with recognition specificity by cMOAT/MRP2. Methods. We examined the inhibitory effect of MTX and 24 analogs on the transport of [3H]–S–(2,4–dinitrophenyl)glutathione by cMOAT/MRP2. The affinity constants of these compounds were compared with their physicochemical parameters. The primary active transport of several compounds was also confirmed. Results. The affinity constants closely correlated with the octanol/water partition coefficient (clogP), and a linear combination of polar and nonpolar surface areas. The affinity for cMOAT/MRP2 also closely correlated with the molecular weight, which also showed a significant correlation with nonpolar surface area and clogP. Conclusions. Recognition by cMOAT/MRP2 depends on a balance of dynamic surface properties between the polar and nonpolar regions of MTX analogs. The so–called “molecular weight threshold” for the cMOAT/MRP2 affinity of these compounds can be explained by their physicochemical parameters, especially their nonpolar surface areas.

5a-Carba-β-D-glucopyranose derivatives as novel sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes.

5a-Carba-β-D-glucopyranose derivatives were synthesized and identified as novel SGLT2-selective inhibitors. These inhibitors exhibited potent SGLT2 inhibition with high selectivity over SGLT1. Among the tested compounds, 6f indicated the most potent hSGLT2 inhibition and the highest selectivity over hSGLT1. Moreover, the pharmacokinetics data also showed that 6h, which had the same aglycon structure as sergliflozin-active (3-active), had a threefold longer half-life time (T(1/2)) than sergliflozin (3) with a high distribution volume in db/db mice. Subsequently, 6h lowered blood glucose levels as much as 3 and showed longer hypoglycemic action than 3 in db/db mice.

C-Aryl 5a-carba-β-d-glucopyranosides as novel sodium glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes.

C-Aryl 5a-carba-β-d-glucopyranose derivatives were synthesized and evaluated for inhibition activity against hSGLT1 and hSGLT2. Modifications to the substituents on the two benzene rings resulted in enhanced hSGLT2 inhibition activity and extremely high hSGLT2 selectivity versus SGLT1. Using the created superimposed model, the reason for the high hSGLT2 selectivity was speculated to be that additional substituents occupied a new space, in a different way than known inhibitors. Among the tested compounds, the ethoxy compound 5h with high hSGLT2 selectivity exhibited more potent and longer hypoglycemic action in db/db mice than our O-carbasugar compound (1) and sergliflozin (2), which could be explained by its improved PK profiles relative to those of the two compounds. These results indicated that 5h might be a promising drug candidate for the treatment of type 2 diabetes.

Discovery of novel motilin antagonists: Conversion of tetrapeptide leads to orally available peptidomimetics.

We successfully discovered peptidomimetic motilin antagonists (17c and 17d) through the improvement of physicochemical properties of a tetrapeptide antagonist (2). Furthermore, with oral administration and based on motilin antagonistic activity, both compounds suppressed motilin-induced colonic and gastric motility in conscious dogs.

Synthesis of tritiated N‐[4‐(2,4‐diaminopteridine‐6‐methyl)‐3,4‐dihydro‐2H‐1,4‐benzothiazine‐7‐carbonyl]‐L‐homo glutamic acid (MX‐68)

Synthesis of tritiated N-[4-(2,4-diaminopteridine-6-methyl)-3,4-dihydro-2H-1,4-benzothiazine-7-carbonyl]-L-homoglutamic acid, [9-3H1]MX-68 (3), is described. [9-3H1]MX-68 (3) was prepared via tritiation at the carbonyl group in 2,4-bis-(butanoylamino)-6-formylpteridine (7) with sodium borotritiide.

Abstract 2533: Design and preclinical profile of CH5183284/Debio 1347, a novel orally available and selective FGFR inhibitor acting on a gatekeeper mutant of FGFR2

The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases (RTKs) comprises four members (FGFR1-4). FGFRs regulate multiple biological processes, such as cell proliferation, migration, apoptosis, and differentiation. Various genetic alterations, as well as overexpression, drive activation of both kinase activity of the receptors and the pathway signaling, which is associated with tumor growth and survival. Therefore, the FGFR family represents an attractive therapeutic target for treating cancer. Here, we report the discovery and the pharmacological profiles of CH5183284/Debio 1347, an orally available and selective inhibitor of FGFR1, 2, and 3. The lead compound CH5183284/Debio 1347 was identified from our original compound library by a high throughput screening program. Chemical modifications, which were guided by 3D-modeling analyses of the lead series and FGFRs, led to identifying an inhibitor that is selective to FGFR1, FGFR2, and FGFR3 (IC50: 9.3 nM, 7.6 nM, and 22 nM), but does not effectively inhibit FGFR4 (IC50: 290 nM), KDR (IC50: 2,100 nM) nor other 34 kinases. To evaluate kinase selectivity further, we used a KINOMEscan panel consisting of 442 kinases including some mutated forms of kinases. At 100 nM, CH5183284/Debio 1347 only bound to 5 kinases in the panel including FGFR1, FGFR2, and FGFR3 (over 80% inhibition to an ATP analog binding). An X-ray crystal structure analysis showed CH5183284/Debio 1347 binding to the ATP-binding site of FGFR1 in DFG-in mode and its interaction with both the hinge region and the backpocket of the protein. CH5183284/Debio 1347 also showed antitumor activity against cancer cell lines harboring genetic alterations in FGFRs in vitro and in xenograft models in mice. In addition, the unique ability of CH5183284/Debio 1347 to inhibit a relevant FGFR2 gatekeeper mutant (V564F) was documented in cellular phosphorylation assays, in vitro cell proliferation assays, and in vivo efficacy studies in a xenograft mouse model. The X-ray crystal structure analysis and modeling studies of the inhibitors, including NVP-BGJ398 and AZD4547, with FGFRs that were used to guide the SAR strategy in the optimization program will be presented and discussed, together with the unique susceptibility of CH5183284/Debio 1347 against a gatekeeper mutant of FGFR2. These findings underline the therapeutic potential of CH5183284/Debio 1347 in patients with FGFR genetic alterations and are the basis for an ongoing early clinical trial in several cancer types. Citation Format: Hirosato Ebiike, Naoki Taka, Yoshito Nakanishi, Nukinori Akiyama, Fumie Sawamura, Kenji Morikami, Masayuki Matsushita, Masayuki Ohmori, Kyouko Takami, Ikumi Hyohdoh, Masami Kohchi, Tadakatsu Hayase, Hiroki Nishii, Nobuya Ishii, Hiroharu Matsuoka. Design and preclinical profile of CH5183284/Debio 1347, a novel orally available and selective FGFR inhibitor acting on a gatekeeper mutant of FGFR2. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2533. doi:10.1158/1538-7445.AM2014-2533