RESUMO
Potent, trans-2-(pyridin-3-yl)cyclopropanecarboxamide-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using fragment-based screening and structure-based design techniques. Multiple crystal structures were obtained of initial fragment leads, and this structural information was utilized to improve the biochemical and cell-based potency of the associated molecules. Many of the optimized compounds exhibited nanomolar antiproliferative activities against human tumor lines in in vitro cell culture experiments. In a key example, a fragment lead (13, KD = 51 µM) was elaborated into a potent NAMPT inhibitor (39, NAMPT IC50 = 0.0051 µM, A2780 cell culture IC50 = 0.000 49 µM) which demonstrated encouraging in vivo efficacy in an HT-1080 mouse xenograft tumor model.
Assuntos
Amidas/síntese química , Antineoplásicos/síntese química , Ciclopropanos/síntese química , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Piridinas/síntese química , Sulfonas/síntese química , Amidas/química , Amidas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Ciclopropanos/química , Ciclopropanos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Transplante de Neoplasias , Conformação Proteica , Piridinas/química , Piridinas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologiaRESUMO
Potent, 1H-pyrazolo[3,4-b]pyridine-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using structure-based design techniques. Many of these compounds exhibited nanomolar antiproliferation activities against human tumor lines in in vitro cell culture experiments, and a representative example (compound 26) demonstrated encouraging in vivo efficacy in a mouse xenograft tumor model derived from the A2780 cell line. This molecule also exhibited reduced rat retinal exposures relative to a previously studied imidazo-pyridine-containing NAMPT inhibitor. Somewhat surprisingly, compound 26 was only weakly active in vitro against mouse and monkey tumor cell lines even though it was a potent inhibitor of NAMPT enzymes derived from these species. The compound also exhibited only minimal effects on in vivo NAD levels in mice, and these changes were considerably less profound than those produced by an imidazo-pyridine-containing NAMPT inhibitor. The crystal structures of compound 26 and the corresponding PRPP-derived ribose adduct in complex with NAMPT were also obtained.
