N-glucosides as human sodium-dependent glucose cotransporter 2 (hSGLT2) inhibitors

Palladium(II)‐Catalyzed Sp3/Sp2γ‐ and δ‐C‐H Functionalization of Aryl Amines using 5‐Methylisoxazole‐3‐Carboxamide as Directing Group

“…Next, we wished to reveal the utility of the 2‐aminodiphenylmethane derivatives ( 25 a , b and 26 e ). In this regard, the 2‐aminodiphenylmethane derivatives 25 b and 26 e were treated with glucose under the reaction conditions reported in a patent work, which targeted the construction of hsGLT2 inhibitor motif ( 3 f , Figure ). Accordingly, the treatment of 25 b and 26 e with glucose afforded the corresponding N ‐glucoside motifs 27 a , b in 30–46% yields (as diastereomers with dr up to 88 : 12, Scheme ).…”

Sodium–glucose cotransporter 2 (SGLT-2) inhibitors: a new antidiabetic drug class

“…A third generation of selective SGLT-2 transporter inhibitors was recently described by the Mitsubishi Tanabe Pharma researchers, being composed of new N-glycosidic derivatives. 15,40 The N-glycosidic aniline analogue 17, designed from the C-glycosidic drug dapagliflozin (1), presented inhibitory potency (IC 50 = 3.9 nM) against the therapeutic target in the same order of magnitude as prototype 1 (IC 50 = 1.12 nM) (Fig. 6).…”

“…The animal's body weight was normalized to 200 g for comparison purposes, resulting in a UGE value of only 93 mg per 200 g BW per day. 40 The drug dapagliflozin (1), for example, in a dosage of 10 mg kg −1 by oral administration, induces a pronounced urinary glucose excretion (UGE = 1900 mg per 200 g BW per day) in the same animal model. 14 A possible explanation for the observed inefficacy of the aniline derivative 17 would be the lability of its N-glycosidic bond in vivo.…”

“…In this context, aiming at the design of a series of more stable N-glycosidic analogues, the authors developed new heterocyclic derivatives, among which the indolic compound 18 stood out, with an adequate in vitro inhibitory potency for SGLT-2 (IC 50 = 7.1 nM) and an in vivo optimized effect on urinary glucose excretion (UGE = 1830 mg per 200 g BW per day) in rats, after an oral administration of a 30 mg kg −1 dose. 40 Subsequent structural modifications in prototype 18 provided the discovery of the indolic N-glycosidic drug candidate TA-1887 (19), with optimized in vitro (IC 50 = 1.4 nM) and in vivo (UGE = 2500 mg per 200 g BW per day) potencies, besides being 164 times more selective for SGLT-2 in comparison with SGLT-1 (Fig. 6).…”

Synthesis of Benzyl C‐Analogues of Dapagliflozin as Potential SGLT2 Inhibitors

“…Nomura, in 2013, probably inspired by the partial success of O ‐glucosides and the aglycon part present in Dapaglifozin, synthesized and evaluated the N ‐glucoside 12 for SGLT2 inhibition. Although 12 exhibited strong hSGLT2 inhibitory activity (IC 50 = 3.9 n m ) comparable to 13 (IC 50 = 5.1 n m ) its hydrolytic stability remained a challenge.…”