Author: Takano, Rieko ; Katagiri, Takahiro ; Shida, Takeshi ; Hirouchi, Masakazu ; Abe, Manabu ; Yamazaki, Mami ; Soma, Kaori ; Nakagami, Yasuhiro ; Toda, Narihiro

Motilin is a 22-amino-acid gastrointestinal (GI) hormone and is involved in the regulation of GI motility through binding to GPR38, the motilin receptor which is expressed on smooth muscle cells in the GI tract. Therefore, GPR38 agonists are expected to be novel gastrointestinal prokinetic agents for the treatment of functional gastrointestinal disorders such as gastroparesis and chronic constipation. We identified a series of N-methylanilide derivatives as novel non-macrolide GPR38 agonists. Among them, 12 di-l-tartrate (DS-3801b) was selected as a clinical candidate for further evaluation.

01 Sep 2017·The Journal of Clinical PharmacologyQ3 · MEDICINE

A Phase 1 Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Oral Doses of DS-3801b, a Motilin Receptor Agonist, in Healthy Subjects

Q3 · MEDICINE

Article

Author: Tao, Ben ; Morimoto, Kiyoshi ; Atiee, George ; Senaldi, Giorgio ; Dennie, Justin ; Warren, Vance

DS-3801b is an orally active, nonmacrolide, selective motilin receptor agonist. The aim of this 2-part first-in-human study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamic effects on proximal and distal gastrointestinal (GI) motility of single oral doses of DS-3801b in healthy subjects. The ¹³ C-octanoate breath test was used to assess gastric emptying (GE), a measure of proximal GI motility. The time to first bowel movement (TTFBM) and the consistency of the first bowel movement according to the Bristol Stool Scale (BSS) were recorded to assess distal GI motility. In part A, 48 subjects received single oral doses of DS-3801b from 1 to 100 mg or placebo (6 DS-3801b, 2 placebo per cohort). In part B, 12 subjects received 50 mg of DS-3801b or placebo to assess GE. DS-3801b is safe and generally well tolerated after doses up to 50 mg, resulting in mild, predominantly GI adverse events. DS-3801a plasma concentrations increase with increasing doses; however, C_max increases greater than dose-proportionally, whereas AUC increases less than dose-proportionally. The double peaks observed are consistent with multiple absorption sites. Results of the ¹³ C-octanoate breath test indicate that DS-3801b accelerates GE. Fifty milligrams of DS-3801b resulted in a 20.8% median reduction in GE T_1/2 and a 20.6% median reduction in GE T_lag compared with placebo. However, this increase in proximal GI motility was not accompanied by an effect on distal GI motility, as indicated by no significant differences in TTFBM and BSS values across DS-3801b dose levels or compared with placebo.

100 Deals associated with DS-3801

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Indication	Highest Phase	Country/Location	Organization	Date
Constipation	Phase 1	JP	Daiichi Sankyo Co., Ltd.	-

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