brain exposure

Aβ42-IN-1 free base (compound 1v), an orally active γ-secretase modulator with high brain exposure, effectively lowers Aβ42 levels with an IC50 of 0.091 μM, and significantly diminishes brain Aβ42 levels in mice. Given these properties, Aβ42-IN-1 free base represents a potential disease-modifying agent for Alzheimer's disease [1].

ATMInhibitor-11 (Compound 1) is an inhibitor of ATM with an IC50 of 0.32 nM. It also inhibits KAP1 phosphorylation with an IC50 of 0.97 nM. This compound exhibits high exposure in the brain, heart, and plasma of ICR mice. Furthermore, ATMInhibitor-11 demonstrates antitumor activity in the NCI-H441 xenograft mouse model.

NRMA-9 is an amide prodrug of small molecule nuclear receptor modulators. It shows high exposure levels in the brain, indicating good penetration of the blood-brain barrier (BBB). NRMA-9 is utilized in research related to central nervous system diseases associated with nuclear receptors, such as Alzheimer's and Parkinson's.

NRMA-I is an amide prodrug of a small molecule nuclear receptor modulator. It demonstrates high brain exposure, indicating effective blood-brain barrier (BBB) penetration. NRMA-I is useful for research into central nervous system diseases related to nuclear receptors, such as Alzheimer's and Parkinson's diseases.

XAP044 is a mGlu7-selective antagonist which inhibits lateral amygdala long term potentiation (LTP) in brain slices from wild type mice with a half-maximal blockade at 88 nm[1].

C19 Ceramide is a naturally occurring ceramide that has been found in J. juncea extracts as well as rat brain and mouse heart.[1],[2],[3] It is elevated in adult and decreased in juvenile whole rat brain extracts by 114 and 37%, respectively, following chronic ethanol exposure.[2] C19 Ceramide is also increased in mouse hearts following administration of angiotensin II.[3]

Phosphoramide mustard cyclohexanamine is the active metabolite of cyclophosphamide, an alkylating agent that cross-links DNA strands, organizes cell division and causes cell death, and has antitumor activity.

FGFR-IN-7 (compound 17) is an orally active, potent FGFR modulator that penetrates the blood-brain barrier, exhibits neuroprotective properties, enhances brain exposure, and decreases the likelihood of phospholidosis, proving valuable for research on neurodegenerative diseases [1].

5-{8-[(3,4'-Difluoro[1,1'-biphenyl]-4-yl)methoxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-N-methylpyridine-2-carboxamide (1o) exhibited high in vitro potency and brain exposure, significantly reduced brain Aβ42 levels, showed no inhibitory effect on cytochrome p450 enzymes, and demonstrated excellent anti-cognitive deficits in AD model mice.

AM-3189 is a potent and selective GPR40 Agonist with minimal CNS penetration, superior pharmacokinetic properties and in vivo efficacy comparable to AMG 837. AM-3189 maintains the in vivo efficacy of AMG 837 while displaying a superior pharmacokinetic profile and minimal CNS exposure. Similar to AMG 837, while highly potent on GPR40, AM-3189 was highly selective over the closely related GPCRs, GPR41 and GPR43. 13kdemonstrated low clearance, moderate volume of distribution, and good oral bioavailability. AM-3189 does not penetrate the rat CNS as indicated by a rat brain to plasma ratio of 0.04 at 3 h after an oral dose of 5 mg kg.

JPC0323 is a dual positive allosteric modulator of the 5-HT2C and 5-HT2A receptors, featuring on-target properties, acceptable plasma exposure, and adequate brain penetration. It is utilized in research pertaining to neurological diseases [1].

WLB-89462 (Compound 20c) is a selective σ2 receptor ligand with a K i of 13 nM, demonstrating neuroprotective properties and the capacity to ameliorate Aβ peptide-induced short-term memory impairment in rats. It exhibits a favorable ADMET profile, featuring good solubility, lack of CYP inhibition, strong metabolic stability, high permeability, effective brain penetration, and significant oral exposure in rodent models [1].

PW0729 (compound 15b) serves as an agonist for the orphan receptor GPR52, facilitating its activation and signaling bias for neuropsychiatric and neurological disorders. Further optimization of its brain exposure characteristics is required for PW0729.