Hashimoto, K; Kawasaki, M; Sumi, H; Yabuki, M; Iwai, K; Yoshida, Sei; Yoshimatsu, Mie; Aoyama, K; Kosugi, Y; Kojima, T; Morishita, Nao; Saito, B; Dougan, DR; Snell, GP; Imamura, S; Ishikawa, T; Miyamoto, N; Oguro, Y; Tomita, D; Shiokawa, Z; Asano, M; Kakei, H; Taya, N; ,
To develop novel inhibitor of apoptosis (IAP) proteins antagonists, we designed a bicyclic octahydropyrrolo-[1,2-a]pyrazine scaffold as a novel proline bioisostere. This design was based on the X-ray co-crystal structure of four N-terminal amino acid residues (AVPI) of the second mitochondria-derived activator of caspase (Smac) with the X-chromosome-linked IAP (XIAP) protein. Lead optimization of this scaffold to improve oral absorption yielded compound 45, which showed potent cellular IAP1 (cIAP1 IC50: 1.3 nM) and XIAP (IC50: 200 nM) inhibitory activity, in addition to potent tumor growth inhibitory activity (GI(50): 1.8 nM) in MDA-MB-231 breast cancer cells. X-ray crystallographic analysis of compound 45 bound to X1AP and to cIAPI was achieved, revealing the various key interactions that contribute to the higher cIAPI affinity of compound 45 over X1AP. Because of its potent IAP inhibitory activities, compound 45 (T-3256336) caused tumor regression in a MDA-MB-231 tumor xenograft model (T/C: -53% at 30 mg/kg).
2 [ 2 (4,4 difluorocyclohexyl) 2 [(n methylalanyl)amino]acetyl] n (3,4 dihydro 2h chromen 4 yl) 7 ethoxyoctahydropyrrolo[1,2 a]pyrazine 3 carboxamide dihydrochloride; 2 [ 2 (4,4 difluorocyclohexyl) 2 [(n methylalanyl)amino]acetyl] n (3,4 dihydro 2h chromen 4 yl) 7 hydroxyoctahydropyrrolo[1,2 a]pyrazine 3 carboxamide dihydrochloride; 2 [ 2 (4,4 difluorocyclohexyl) 2 [(n methylalanyl)amino]acetyl] n (3,4 dihydro 2h chromen 4 yl) 7,7 difluorooctahydropyrrolo[1,2 a]pyrazine 3 carboxamide dihydrochloride; 2 [2 (4,4 difluorocyclohexyl) 2 [(n methylalanyl)amino]acetyl] n (3,4 dihydro 2h chromen 4 yl)octahydropyrrolo[1,2 a]pyrazine 3 carboxamide dihydrochloride; 2 [2 cyclohexyl 2 [(n methylalanyl)amino]acetyl] n (1 phenylethyl)octahydropyrrolo[1,2 a]pyrazine 3 carboxamide dihydrochloride; 2 [2 cyclohexyl 2 [(n methylalanyl)amino]acetyl] n (1,2,3,4 tetrahydronaphthalen 1 yl)octahydropyrrolo[1,2 a]pyrazine 3 carboxamide dihydrochloride; 2 [2 cyclohexyl 2 [(n methylalanyl)amino]acetyl] n (3,4 dihydro 2h chromen 4 yl)octahydropyrrolo[1,2 a]pyrazine 3 carboxamide dihydrochloride; 2 [2 cyclohexyl 2 [(n methylalanyl)amino]acetyl] n (4 oxo 1,2,3,4 tetrahydronaphthalen 1 yl)octahydropyrrolo[1,2 a]pyrazine 3 carboxamide dihydrochloride; 2 [2 cyclohexyl 2 [(n methylalanyl)amino]acetyl] n (4,4 difluoro 1,2,3,4 tetrahydronaphthalen 1 yl)octahydropyrrolo[1,2 a]pyrazine 3 carboxamide dihydrochloride; 2 tert butyl 3 ethyl hexahydropyrrolo[1,2 a]pyrazine 2,3(1h)dicarboxylate; at 406; benzyl [1 (4,4 difluorocyclohexyl) 2 [3 (3,4 dihydro 2h chromen 4 ylcarbamoyl)hexahydropyrrolo[1,2 a]pyrazin 2(1h) yl] 2 oxoethyl]carbamate; benzyl [2 [3 (3,4 dihydro 2h chromen 4 ylcarbamoyl)hexahydropyrrolo[1,2 a]pyrazin 2(1h) yl] 2 oxo 1 phenylethyl]carbamate; benzyl[1 (4,4 difluorocyclohexyl) 2 [3 (3,4 dihydro 2h chromen 4 ylcarbamoyl) 7 ethoxyhexahydropyrrolo[1,2 a]pyrazin 2(1h)yl] 2 oxoethyl]carbamate; benzyl[1 (4,4 difluorocyclohexyl) 2 [3 (3,4 dihydro 2h chromen 4 ylcarbamoyl) 7 hydroxyhexahydropyrrolo[1,2 a]pyrazin 2(1h)yl] 2 oxoethyl]carbamate; benzyl[1 (4,4 difluorocyclohexyl) 2 [3 (3,4 dihydro 2h chromen 4 ylcarbamoyl) 7,7 difluorohexahydropyrrolo[1,2 a]pyrazin 2(1h)yl] 2 oxoethyl]carbamate; birinapant; gdc 0152; hgs 1029; inhibitor of apoptosis protein; inhibitor of apoptosis protein antagonist; lcl 161; n (3,4 dihydro 2h chromen 4 yl) 2 [2 [(n methylalanyl)amino] 2 (tetrahydro 2h pyran 4 yl)acetyl]octahydropyrrolo[1,2 a]pyrazine 3 carboxamide dihydrochloride; n (3,4 dihydro 2h chromen 4 yl) 2 [2 [(n methylalanyl)amino] 2 phenylacetyl]octahydropyrrolo[1,2 a]pyrazine 3 carboxamide dihydrochloride; octahydropyrrolo[1,2 a]pyrazine derivative; proline derivative; protein inhibitor; second mitochondrial activator of caspase; t 3256336; tert butyl 3 (3,4 dihydro 2h chromen 4 ylcarbamoyl) 7 ethoxyhexahydropyrrolo[1,2 a]pyrazine 2(1h)carboxylate; tert butyl 3 (3,4 dihydro 2h chromen 4 ylcarbamoyl) 7 hydroxyhexahydropyrrolo[1,2 a]pyrazine 2(1h)carboxylate; tert butyl 3 (3,4 dihydro 2h chromen 4 ylcarbamoyl) 7,7 difluorohexahydropyrrolo[1,2 a]pyrazine 2(1h)carboxylate; tert butyl 3 (3,4 dihydro 2h chromen 4 ylcarbamoyl)hexahydropyrrolo[1,2 a]pyrazine 2(1h)carboxylate; unclassified drug; unindexed drug; X linked inhibitor of apoptosis; animal experiment; animal model; apoptosis; article; binding affinity; cancer cell culture; cancer inhibition; controlled study; crystal structure; drug absorption; drug bioavailability; drug design; drug potency; drug protein binding; drug selectivity; drug structure; drug synthesis; female; human; human cell; IC 50; mouse; nonhuman; protein domain; protein structure; structure activity relation; tumor regression; tumor xenograft; X ray crystallography; Bicyclo Compounds, Heterocyclic; Crystallography, X-Ray; Drug Design; Inhibitor of Apoptosis Proteins; Magnetic Resonance Spectroscopy; Models, Molecular; Oligopeptides; Peptidomimetics; Proline