Robust Translation of γ-Secretase Modulator Pharmacology across Preclinical Species and Human Subjects

  • J Pharmacol Exp Ther. 2016 Jul;358(1):125-37. doi: 10.1124/jpet.116.232249.
Jeremy H Toyn  1 ,  Kenneth M Boy  1 ,  Joseph Raybon  1 ,  Jere E Meredith Jr  1 ,  Alan S Robertson  1 ,  Valerie Guss  1 ,  Nina Hoque  1 ,  Francis Sweeney  1 ,  Xiaoliang Zhuo  1 ,  Wendy Clarke  1 ,  Kimberly Snow  1 ,  R Rex Denton  1 ,  Dmitry Zuev  1 ,  Lorin A Thompson  1 ,  John Morrison  1 ,  James Grace  1 ,  Flora Berisha  1 ,  Michael Furlong  1 ,  Jun-Sheng Wang  1 ,  Kimberly A Lentz  1 ,  Ramesh Padmanabha  1 ,  Lynda Cook  1 ,  Cong Wei  1 ,  Dieter M Drexler  1 ,  John E Macor  1 ,  Charlie F Albright  1 ,  Maciej Gasior  1 ,  Richard E Olson  1 ,  Quan Hong  1 ,  Holly D Soares  1 ,  Malaz AbuTarif  1 ,  Michael K Ahlijanian  2
Affiliations
  • 1. Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.).
  • 2. Yale University, New Haven, Connecticut (J.H.T.); Bristol-Myers Squibb, Wallingford, Connecticut (K.M.B, J.R., Je.E.M., A.S.R., V.G., N.H., F.S., X.Z., W.C., K.S., R.R.D., L.A.T., J.M., J.G., K.A.L., R.P., L.C., D.M.D., C.F.A., R.E.O., M.K.A.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S., C.W.); Cantor Colburn LLP, Hartford, Connecticut (D.Z.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.F.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Bristol-Myers Squibb, Pennington, New Jersey (Jo.E.M., H.D.S., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); and Eisai, Woodcliff Lake, New Jersey (Q.H.) [email protected].
PMID: 27189974 DOI: 10.1124/jpet.116.232249
Abstract

The Amyloid-β peptide (Aβ)-in particular, the 42-amino acid form, Aβ1-42-is thought to play a key role in the pathogenesis of Alzheimer's Disease (AD). Thus, several therapeutic modalities aiming to inhibit Aβ synthesis or increase the clearance of Aβ have entered clinical trials, including γ-secretase inhibitors, anti-Aβ antibodies, and Amyloid-β precursor protein cleaving enzyme inhibitors. A unique class of small molecules, γ-secretase modulators (GSMs), selectively reduce Aβ1-42 production, and may also decrease Aβ1-40 while simultaneously increasing one or more shorter Aβ Peptides, such as Aβ1-38 and Aβ1-37. GSMs are particularly attractive because they do not alter the total amount of Aβ Peptides produced by γ-secretase activity; they spare the processing of other γ-secretase substrates, such as Notch; and they do not cause accumulation of the potentially toxic processing intermediate, β-C-terminal fragment. This report describes the translation of pharmacological activity across species for two novel GSMs, (S)-7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (BMS-932481) and (S,Z)-17-(4-chloro-2-fluorophenyl)-34-(3-methyl-1H-1,2,4-triazol-1-yl)-16,17-dihydro-15H-4-oxa-2,9-diaza-1(2,4)-cyclopenta[d]pyrimidina-3(1,3)-benzenacyclononaphan-6-ene (BMS-986133). These GSMs are highly potent in vitro, exhibit dose- and time-dependent activity in vivo, and have consistent levels of pharmacological effect across rats, dogs, monkeys, and human subjects. In rats, the two GSMs exhibit similar pharmacokinetics/pharmacodynamics between the brain and cerebrospinal fluid. In all species, GSM treatment decreased Aβ1-42 and Aβ1-40 levels while increasing Aβ1-38 and Aβ1-37 by a corresponding amount. Thus, the GSM mechanism and central activity translate across preclinical species and humans, thereby validating this therapeutic modality for potential utility in AD.

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