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Discovery of First Branched-Chain Ketoacid Dehydrogenase Kinase (BDK) Inhibitor Clinical Candidate PF-07328948.

Autor: Filipski KJ; Pfizer Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Martinez-Alsina LA; Pfizer Research & Development, 558 Eastern Point Road, Groton, Connecticut 06340, United States., Reese MR; Pfizer Research & Development, 558 Eastern Point Road, Groton, Connecticut 06340, United States., Evrard E; Pfizer Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Buzon LM; Pfizer Research & Development, 558 Eastern Point Road, Groton, Connecticut 06340, United States., Cameron KO; Pfizer Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Zhang Y; Pfizer Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Coffman KJ; Pfizer Research & Development, 558 Eastern Point Road, Groton, Connecticut 06340, United States., Bradow J; Pfizer Research & Development, 558 Eastern Point Road, Groton, Connecticut 06340, United States., Kormos BL; Pfizer Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Liu S; Pfizer Research & Development, 558 Eastern Point Road, Groton, Connecticut 06340, United States., Knafels JD; Pfizer Research & Development, 558 Eastern Point Road, Groton, Connecticut 06340, United States., Sahasrabudhe PV; Pfizer Research & Development, 558 Eastern Point Road, Groton, Connecticut 06340, United States., Chen J; Pfizer Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Kalgutkar AS; Pfizer Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Bessire AJ; Pfizer Research & Development, 558 Eastern Point Road, Groton, Connecticut 06340, United States., Orozco CC; Pfizer Research & Development, 558 Eastern Point Road, Groton, Connecticut 06340, United States., Balesano A; Pfizer Research & Development, 558 Eastern Point Road, Groton, Connecticut 06340, United States., Cerny MA; Pfizer Research & Development, 558 Eastern Point Road, Groton, Connecticut 06340, United States., Bollinger E; Pfizer Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Reyes AR; Pfizer Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Laforest B; Pfizer Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Rosado A; Pfizer Research & Development, 558 Eastern Point Road, Groton, Connecticut 06340, United States., Williams G; Pfizer Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Marshall M; Pfizer Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Tam Neale K; Pfizer Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Chen X; Pfizer Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Hirenallur-Shanthappa D; Pfizer Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Stansfield JC; Pfizer Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Groarke J; Pfizer Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Qiu R; Pfizer Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Karas S; Pfizer Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Roth Flach RJ; Pfizer Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Esler WP; Pfizer Research & Development, 558 Eastern Point Road, Groton, Connecticut 06340, United States.

Publikováno v: Journal of medicinal chemistry [J Med Chem] 2024 Nov 19. Date of Electronic Publication: 2024 Nov 19.

Small molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels.

Autor: Roth Flach RJ; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA. rachel.rothflach@pfizer.com., Bollinger E; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Reyes AR; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Laforest B; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Kormos BL; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Liu S; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Reese MR; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Martinez Alsina LA; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Buzon L; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Zhang Y; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Bechle B; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Rosado A; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Sahasrabudhe PV; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Knafels J; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Bhattacharya SK; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Omoto K; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Stansfield JC; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Hurley LD; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Song L; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Luo L; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Breitkopf SB; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Monetti M; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Cunio T; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Tierney B; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Geoly FJ; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Delmore J; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Siddall CP; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Xue L; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Yip KN; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Kalgutkar AS; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Miller RA; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Zhang BB; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Filipski KJ; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA. kevin.filipski@pfizer.com.

Publikováno v: Nature communications [Nat Commun] 2023 Aug 09; Vol. 14 (1), pp. 4812. Date of Electronic Publication: 2023 Aug 09.

BDK inhibition acts as a catabolic switch to mimic fasting and improve metabolism in mice.

Autor: Bollinger E; Internal Medicine Research Unit, Pfizer Inc, Cambridge MA 02139, USA., Peloquin M; Internal Medicine Research Unit, Pfizer Inc, Cambridge MA 02139, USA., Libera J; Internal Medicine Research Unit, Pfizer Inc, Cambridge MA 02139, USA., Albuquerque B; Internal Medicine Research Unit, Pfizer Inc, Cambridge MA 02139, USA., Pashos E; Internal Medicine Research Unit, Pfizer Inc, Cambridge MA 02139, USA., Shipstone A; Inflammation & Immunology Research Unit, Pfizer Inc, Cambridge MA 02139, USA., Hadjipanayis A; Inflammation & Immunology Research Unit, Pfizer Inc, Cambridge MA 02139, USA., Sun Z; Internal Medicine Research Unit, Pfizer Inc, Cambridge MA 02139, USA., Xing G; Internal Medicine Research Unit, Pfizer Inc, Cambridge MA 02139, USA., Clasquin M; Internal Medicine Research Unit, Pfizer Inc, Cambridge MA 02139, USA., Stansfield JC; Early Clinical Development, Pfizer Inc, Cambridge MA 02139, USA., Tierney B; Medicine Design, Pfizer Inc, Groton, CT 06340, USA., Gernhardt S; Medicine Design, Pfizer Inc, Groton, CT 06340, USA., Siddall CP; Internal Medicine Research Unit, Pfizer Inc, Cambridge MA 02139, USA., Greizer T; Internal Medicine Research Unit, Pfizer Inc, Cambridge MA 02139, USA., Geoly FJ; Drug Safety Research and Development, Pfizer Inc, Groton CT 06340, USA., Vargas SR; Drug Safety Research and Development, Pfizer Inc, Groton CT 06340, USA., Gao LC; Internal Medicine Research Unit, Pfizer Inc, Cambridge MA 02139, USA., Williams G; Internal Medicine Research Unit, Pfizer Inc, Cambridge MA 02139, USA., Marshall M; Internal Medicine Research Unit, Pfizer Inc, Cambridge MA 02139, USA., Rosado A; Medicine Design, Pfizer Inc, Groton, CT 06340, USA., Steppan C; Medicine Design, Pfizer Inc, Groton, CT 06340, USA., Filipski KJ; Medicine Design, Pfizer Inc, Cambridge MA 02139, USA., Zhang BB; Internal Medicine Research Unit, Pfizer Inc, Cambridge MA 02139, USA., Miller RA; Internal Medicine Research Unit, Pfizer Inc, Cambridge MA 02139, USA., Roth Flach RJ; Internal Medicine Research Unit, Pfizer Inc, Cambridge MA 02139, USA. Electronic address: rachel.rothflach@pfizer.com.

Publikováno v: Molecular metabolism [Mol Metab] 2022 Dec; Vol. 66, pp. 101611. Date of Electronic Publication: 2022 Oct 08.