Preclinical Characterization of ( R )-3-((3 S ,4 S )-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169), a Novel, Intravenous, Glutamate N -Methyl-d-Aspartate 2B Receptor Negative Allosteric Modulator with Potential in Major Depressive Disorder.

Autor: Bristow LJ; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.) Linda.bristow@sunovion.com lawrence.marcin@bms.com., Gulia J; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Weed MR; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Srikumar BN; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Li YW; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Graef JD; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Naidu PS; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Sanmathi C; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Aher J; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Bastia T; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Paschapur M; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Kalidindi N; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Kumar KV; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Molski T; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Pieschl R; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Fernandes A; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Brown JM; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Sivarao DV; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Newberry K; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Bookbinder M; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Polino J; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Keavy D; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Newton A; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Shields E; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)., Simmermacher J; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. 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I.I.)., Li J; Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. 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Jazyk: angličtina
Zdroj: The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2017 Dec; Vol. 363 (3), pp. 377-393. Date of Electronic Publication: 2017 Sep 27.
DOI: 10.1124/jpet.117.242784
Abstrakt: ( R )-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3 S ,4 S )-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate (BMS-986163) were identified from a drug discovery effort focused on the development of novel, intravenous glutamate N -methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD). BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (K i = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human N -methyl-d-aspartate receptor subtypes (IC 50 = 24.1 nM). BMS-986169 weakly inhibited human ether-a-go-go-related gene channel activity (IC 50 = 28.4 μ M) and had negligible activity in an assay panel containing 40 additional pharmacological targets. Intravenous administration of BMS-986169 or BMS-986163 dose-dependently increased GluN2B receptor occupancy and inhibited in vivo [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[ a,d ]cyclohepten-5,10-imine ([3H]MK-801) binding, confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency, and increased ex vivo hippocampal long-term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD.
(Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze: MEDLINE
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