Literature DB >> 24900185

Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable γ-Secretase Inhibitor.

Kevin W Gillman1, John E Starrett1, Michael F Parker1, Kai Xie1, Joanne J Bronson1, Lawrence R Marcin1, Kate E McElhone1, Carl P Bergstrom1, Robert A Mate1, Richard Williams2, Jere E Meredith3, Catherine R Burton3, Donna M Barten3, Jeremy H Toyn3, Susan B Roberts3, Kimberley A Lentz4, John G Houston3, Robert Zaczek3, Charles F Albright3, Carl P Decicco1, John E Macor1, Richard E Olson1.   

Abstract

During the course of our research efforts to develop a potent and selective γ-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-β precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of γ-secretase (Aβ40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced Aβ40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.

Entities:  

Keywords:  Alzheimer's; amyloid; brain penetrant; clinical candidate; oxadiazole; γ-Secretase

Year:  2010        PMID： 24900185      PMCID： PMC4007960          DOI： 10.1021/ml1000239

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  17 in total

Review 1.  Notch signaling: cell fate control and signal integration in development.

Authors:  S Artavanis-Tsakonas; M D Rand; R J Lake
Journal:  Science       Date:  1999-04-30       Impact factor: 47.728

Review 2.  Notch signaling: a dance of proteins changing partners.

Authors:  T Kadesch
Journal:  Exp Cell Res       Date:  2000-10-10       Impact factor: 3.905

3.  Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor.

Authors:  George H Searfoss; William H Jordan; David O Calligaro; Elizabeth J Galbreath; Linda M Schirtzinger; Brian R Berridge; Hong Gao; Marnie A Higgins; Patrick C May; Timothy P Ryan
Journal:  J Biol Chem       Date:  2003-08-29       Impact factor: 5.157

4.  Amino-caprolactam derivatives as gamma-secretase inhibitors.

Authors:  Michael F Parker; Joanne J Bronson; Donna M Barten; Jason A Corsa; Wengsheng Du; Kevin M Felsenstein; Valerie L Guss; Darcy Izzarelli; Alice Loo; Kate E McElhone; Larry R Marcin; Ramesh Padmanabha; Roger Pak; Craig T Polson; Jeremy H Toyn; Sam Varma; Jian Wang; Victoria Wong; Ming Zheng; Susan B Roberts
Journal:  Bioorg Med Chem Lett       Date:  2007-08-26       Impact factor: 2.823

5.  Reductions in beta-amyloid concentrations in vivo by the gamma-secretase inhibitors BMS-289948 and BMS-299897.

Authors:  Jeffery J Anderson; Greg Holtz; Patricia P Baskin; Mary Turner; Blake Rowe; Bowei Wang; Maria Z Kounnas; Bruce T Lamb; Donna Barten; Kevin Felsenstein; Ian McDonald; Kumar Srinivasan; Ben Munoz; Steven L Wagner
Journal:  Biochem Pharmacol       Date:  2005-01-07       Impact factor: 5.858

6.  Novel benzodiazepine receptor partial agonists: oxadiazolylimidazobenzodiazepines.

Authors:  F Watjen; R Baker; M Engelstoff; R Herbert; A MacLeod; A Knight; K Merchant; J Moseley; J Saunders; C J Swain
Journal:  J Med Chem       Date:  1989-10       Impact factor: 7.446

7.  Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation.

Authors:  Joseph Milano; Jenny McKay; Claude Dagenais; Linda Foster-Brown; Francois Pognan; Reto Gadient; Robert T Jacobs; Anna Zacco; Barry Greenberg; Paul J Ciaccio
Journal:  Toxicol Sci       Date:  2004-08-19       Impact factor: 4.849

Review 8.  Deciphering the molecular basis of memory failure in Alzheimer's disease.

Authors:  Dominic M Walsh; Dennis J Selkoe
Journal:  Neuron       Date:  2004-09-30       Impact factor: 17.173

9.  The amyloid-beta rise and gamma-secretase inhibitor potency depend on the level of substrate expression.

Authors:  Catherine R Burton; Jere E Meredith; Donna M Barten; Margi E Goldstein; Carol M Krause; Cathy J Kieras; Lisa Sisk; Lawrence G Iben; Craig Polson; Mark W Thompson; Xu-Alan Lin; Jason Corsa; Tracey Fiedler; Maria Pierdomenico; Yang Cao; Arthur H Roach; Joseph L Cantone; Michael J Ford; Dieter M Drexler; Richard E Olson; Michael G Yang; Carl P Bergstrom; Kate E McElhone; Joanne J Bronson; John E Macor; Yuval Blat; Robert H Grafstrom; Andrew M Stern; Dietmar A Seiffert; Robert Zaczek; Charles F Albright; Jeremy H Toyn
Journal:  J Biol Chem       Date:  2008-06-23       Impact factor: 5.157

10.  Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation.

Authors:  Gwendolyn T Wong; Denise Manfra; Frederique M Poulet; Qi Zhang; Hubert Josien; Thomas Bara; Laura Engstrom; Maria Pinzon-Ortiz; Jay S Fine; Hu-Jung J Lee; Lili Zhang; Guy A Higgins; Eric M Parker
Journal:  J Biol Chem       Date:  2004-01-06       Impact factor: 5.157
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  46 in total

1.  MH84: A Novel γ-Secretase Modulator/PPARγ Agonist--Improves Mitochondrial Dysfunction in a Cellular Model of Alzheimer's Disease.

Authors:  Maximilian Pohland; Stephanie Hagl; Maren Pellowska; Mario Wurglics; Manfred Schubert-Zsilavecz; Gunter P Eckert
Journal:  Neurochem Res       Date:  2015-12-31       Impact factor: 3.996

Review 2.  Presenilins and γ-secretase: structure, function, and role in Alzheimer Disease.

Authors:  Bart De Strooper; Takeshi Iwatsubo; Michael S Wolfe
Journal:  Cold Spring Harb Perspect Med       Date:  2012-01       Impact factor: 6.915

3.  γ-Secretase Inhibitors and Modulators Induce Distinct Conformational Changes in the Active Sites of γ-Secretase and Signal Peptide Peptidase.

Authors:  Natalya Gertsik; De-Ming Chau; Yue-Ming Li
Journal:  ACS Chem Biol       Date:  2015-06-10       Impact factor: 5.100

Review 4.  γ-Secretase and its modulators: Twenty years and beyond.

Authors:  Weiming Xia
Journal:  Neurosci Lett       Date:  2019-02-11       Impact factor: 3.046

5.  BMS-708,163 targets presenilin and lacks notch-sparing activity.

Authors:  Christina J Crump; Suita V Castro; Feng Wang; Nikolay Pozdnyakov; T Eric Ballard; Sangram S Sisodia; Kelly R Bales; Douglas S Johnson; Yue-Ming Li
Journal:  Biochemistry       Date:  2012-09-04       Impact factor: 3.162

6.  Has inhibition of Aβ production adequately been tested as therapeutic approach in mild AD? A model-based meta-analysis of γ-secretase inhibitor data.

Authors:  Camilla Niva; Joanna Parkinson; Fredrik Olsson; Erno van Schaick; Johan Lundkvist; Sandra A G Visser
Journal:  Eur J Clin Pharmacol       Date:  2013-01-04       Impact factor: 2.953

Review 7.  Toward the structure of presenilin/γ-secretase and presenilin homologs.

Authors:  Michael S Wolfe
Journal:  Biochim Biophys Acta       Date:  2013-12

Review 8.  γ-Secretase inhibitors and modulators: Mechanistic insights into the function and regulation of γ-Secretase.

Authors:  Pengju Nie; Abhishek Vartak; Yue-Ming Li
Journal:  Semin Cell Dev Biol       Date:  2020-04-02       Impact factor: 7.727

Review 9.  Target- and mechanism-based therapeutics for neurodegenerative diseases: strength in numbers.

Authors:  Paul C Trippier; Kristin Jansen Labby; Dustin D Hawker; Jan J Mataka; Richard B Silverman
Journal:  J Med Chem       Date:  2013-03-27       Impact factor: 7.446

10.  A novel high throughput 1536-well Notch1 γ -secretase AlphaLISA assay.

Authors:  De-Ming Chau; David Shum; Constantin Radu; Bhavneet Bhinder; David Gin; M Lane Gilchrist; Hakim Djaballah; Yue-Ming Li
Journal:  Comb Chem High Throughput Screen       Date:  2013-07       Impact factor: 1.339
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