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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 358; no. 1; pp. 125 - 137
• Main Authors: Toyn, Jeremy H., Boy, Kenneth M., Raybon, Joseph, Meredith, Jere E., Robertson, Alan S., Guss, Valerie, Hoque, Nina, Sweeney, Francis, Zhuo, Xiaoliang, Clarke, Wendy, Snow, Kimberly, Denton, R. Rex, Zuev, Dmitry, Thompson, Lorin A., Morrison, John, Grace, James, Berisha, Flora, Furlong, Michael, Wang, Jun-Sheng, Lentz, Kimberly A., Padmanabha, Ramesh, Cook, Lynda, Wei, Cong, Drexler, Dieter M., Macor, John E., Albright, Charlie F., Gasior, Maciej, Olson, Richard E., Hong, Quan, Soares, Holly D., AbuTarif, Malaz, Ahlijanian, Michael K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2016; The American Society for Pharmacology and Experimental Therapeutics
• Subjects: Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - cerebrospinal fluid; Amyloid beta-Peptides - genetics; Amyloid Precursor Protein Secretases - metabolism; Aniline Compounds - chemistry; Aniline Compounds - pharmacokinetics; Aniline Compounds - pharmacology; Animals; Brain - drug effects; Brain - enzymology; Brain - metabolism; Bridged-Ring Compounds - chemistry; Bridged-Ring Compounds - pharmacokinetics; Bridged-Ring Compounds - pharmacology; Cell Line; Dogs; Dose-Response Relationship, Drug; Drug Discovery and Translational Medicine; Drug Evaluation, Preclinical; Female; Humans; Macaca fascicularis; Pyrimidines - chemistry; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Rats, Sprague-Dawley; Receptors, Notch - metabolism; Species Specificity; Tissue Distribution; GSM; ABEC; APP; BMS-698861; PK/PD; AD; NSAID; BMS-299897; FAD; BMS-986133; MS-MS; AUC; Aβ; BMS-932481; CSF; GSI; ELISA
• ISSN: 0022-3565; 1521-0103; 1521-0103
• DOI: 10.1124/jpet.116.232249

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.