title: Dihydropyrrolo[2,3-d]pyrimidines: Selective Toll-Like Receptor 9 Antagonists from Scaffold Morphing Efforts.
abstract: Toll-like receptors (TLRs) play important roles in the innate immune system. In fact, recognition of endogenous immune complexes containing self-nucleic acids as pathogen- or damage-associated molecular patterns contributes to certain autoimmune diseases, and inhibition of these recognition signals is expected to have therapeutic value. We identified dihydropyrrolo[2,3-d]pyrimidines as novel selective TLR9 antagonists with high aqueous solubility. A structure-activity relationship study of a known TLR9 antagonist led to the promising compound 18, which showed potent TLR9 antagonistic activity, sufficient aqueous solubility for parenteral formulation, and druggable properties. Compound 18 suppressed the production of the proinflammatory cytokine IL-6 in CpG-induced mouse model. It is therefore believed that compound 18 has great potential in the treatment of TLR9-mediated systemic uncontrollable inflammatory response like sepsis.
authors.affiliation: Sumitomo Dainippon Pharma Co., Ltd. , 3-1-98 Kasugade Naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Sumitomo Dainippon Pharma Co., Ltd. , 3-1-98 Kasugade Naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Kasai
authors.affiliation: Sumitomo Dainippon Pharma Co., Ltd. , 3-1-98 Kasugade Naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Tomizawa
authors.affiliation: Sumitomo Dainippon Pharma Co., Ltd. , 3-1-98 Kasugade Naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Aoki
authors.affiliation: Sumitomo Dainippon Pharma Co., Ltd. , 3-1-98 Kasugade Naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Eiho
authors.affiliation: Sumitomo Dainippon Pharma Co., Ltd. , 3-1-98 Kasugade Naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Isobe
authors.affiliation: Sumitomo Dainippon Pharma Co., Ltd. , 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Asano
keywords: LLE; Toll-like receptor 9; autoimmune disease; dihydropyrrolo[2,3-d]pyrimidine; sepsis