作者: Itai, Akiko ; Muto, Susumu ; Tokuyama, Ryukou ; Naya, Noriyuki ; Fukao, Keita ; Fukasawa, Hiroshi ; Ohara, Takafumi ; Kato, Terukazu ; Matsumura, Ken-Ichi

Peroxisome proliferator-activated receptor δ (PPARδ) is considered to be a pharmaceutical target to treat metabolic diseases including atherosclerosis, but there is no PPARδ agonist available for clinical use. We have previously reported the discovery of piperidinyl/piperazinyl benzothiazole derivatives as a new series of PPARδ agonists using docking-based virtual screening methods. In the present study, we found that introduction of a pyrrolidine group into the 4-position of their central piperidine rings enhances hPPARδ activity and subtype selectivity. This led to the discovery of 21 having strong PPARδ agonist activity (EC₅₀ = 3.6 nM) with excellent ADME properties. Furthermore, 21 significantly suppressed atherosclerosis progression by 50-60% with reduction of the serum level of MCP-1 in LDLr-KO mice.

2011-11-18·Organic Process Research & Development

Pilot Plant Preparation of tert-Butyl-4-(2-hydroxyethyl)-4-(pyrrolidin-1-yl)-piperidine-1-carboxylate, An Intermediate of Novel Antiarteriosclerotics, Via a Safe, Scalable Reformatsky-Type Reaction

作者: Osato, Hiroshi ; Oyama, Takao ; Kabaki, Mikio ; Osaki, Motonari ; Nishi, Koichi ; Hida, Takemasa ; Takagi, Youhei

Reported here is a safe, scalable process via a Reformatsky-type reaction of iminium salt (4) followed by Red-Al reduction giving tert-butyl-4-(2-hydroxyethyl)-4-(pyrrolidin-1-yl)-piperidine-1-carboxylate (6), an intermediate of novel antiarteriosclerotics (1).The key points of this safe process are the use of triflouroacetyl (TFA) for the iminium salt formation, vigorous stirring for the Reformatsky reaction, and slow addition of Me bromoacetate.Pilot manufacturing on the 500 L scale was achieved.

Journal of Medicinal Chemistry

Design, Synthesis, and Anti-Inflammatory Evaluation of a Novel PPARδ Agonist with a 4-(1-Pyrrolidinyl)piperidine Structure

作者: Itai, Akiko ; Kato, Terukazu ; Naya, Noriyuki ; Fukao, Keita ; Muto, Susumu ; Ohara, Takafumi ; Tokuyama, Ryukou ; Fukasawa, Hiroshi ; Matsumura, Ken-ichi

Peroxisome proliferator-activated receptor δ (PPARδ) is considered to be a pharmaceutical target to treat metabolic diseases including atherosclerosis, but there is no PPARδ agonist available for clin. use.We have previously reported the discovery of piperidinyl/piperazinyl benzothiazole derivatives as a new series of PPARδ agonists using docking-based virtual screening methods.In the present study, we found that introduction of a pyrrolidine group into the 4-position of their central piperidine rings enhances hPPARδ activity and subtype selectivity.This led to the discovery of 21 having strong PPARδ agonist activity (EC50 = 3.6 nM) with excellent ADME properties.Furthermore, 21 significantly suppressed atherosclerosis progression by 50-60% with reduction of the serum level of MCP-1 in LDLr-KO mice.

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