High CNS Penetration Research Articles

Neuroimaging of HIV-associated neurocognitive disorders.

A significant increase in the incidence of cognitive impairment in HIV/AIDS patients has been continuously observed. Consequently, three classification categories of cognitive impairment have been proposed: asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND), that correspond to the mild and intermediate forms, and HIV-associated dementia (HAD) for the most severe cases. HIV-associated neurocognitive disorders (HAND) is a broad term that encompasses these three categories. Moreover, the application of neuroimaging methods has led to a major breakthrough in understanding of the neurological changes in HIV, providing greater reliability in the exclusion of associated diseases and allowing earlier diagnosis. Therefore, abnormalities and/or specific neuroimaging elements may soon be incorporated into the HAND classification criteria, which will be of great value in the management of these diseases, including in the optimization of high CNS penetration antiretroviral regimens.

Spotlight on the July 8 Issue

In acute sera from 199 patients with Guillain-Barre syndrome, immunoglobulin G antibodies to glycolipids and ganglioside complexes were tested against individual antigens from single glycolipids and a neutral glycolipid, and antigens from the combination of 2 different glycolipids. Antibodies to glycolipids were associated with acute motor axonal or conduction block neuropathies but not acute inflammatory demyelinating polyneuropathy. See p. 118 Using observational data from individuals with HIV, the authors found that initiating an antiretroviral regimen with high CNS penetration increases the risk of HIV dementia but not other AIDS-defining neurologic conditions. …

Discovery of the First M5-Selective and CNS Penetrant Negative Allosteric Modulator (NAM) of a Muscarinic Acetylcholine Receptor: (S)-9b-(4-Chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375)

A functional high throughput screen and subsequent multidimensional, iterative parallel synthesis effort identified the first muscarinic acetylcholine receptor (mAChR) negative allosteric modulator (NAM) selective for the M5 subtype. ML375 is a highly selective M5 NAM with submicromolar potency (human M5 IC50 = 300 nM, rat M5 IC50 = 790 nM, M1-M4 IC50 > 30 μM), excellent multispecies PK, high CNS penetration, and enantiospecific inhibition.

Discovery and structure–activity relationship of 1,3-cyclohexyl amide derivatives as novel mGluR5 negative allosteric modulators

A novel series of trans-1,3-cyclohexyl diamides was discovered and characterized as mGluR5 negative allosteric modulators (NAMs) lacking an alkyne moiety. Conformational constraint of one of the amide bonds in the diamide template led to a spirooxazoline template. A representative compound (24d) showed good in vitro potency, high CNS penetration and, upon subcutaneous dosing, demonstrated efficacy in the mouse marble burying test, generally used as indicative of potential anxiolytic activity.

Identification of benzoxazole analogs as novel, S1P3 sparing S1P1 agonists

A novel series of benzoxazole-derived S1P1 agonists were designed based on scaffold hopping molecular design strategy combined with computational approaches. Extensive SAR studies led to the discovery of compound 17d as a selective S1P1 agonist (over S1P3) with high CNS penetration and favorable DMPK properties. 17d also demonstrated in vivo pharmacological efficacy to reduce blood lymphocyte in mice after oral administration.

γ-Carbolines: A novel class of cannabinoid agonists with high aqueous solubility and restricted CNS penetration

An oral, peripherally restricted CB1/CB2 agonist could provide an interesting approach to treat chronic pain by harnessing the analgesic properties of cannabinoids but without the well-known central side effects. γ-Carbolines are a novel class of potent mixed CB1/CB2 agonists characterized by attractive physicochemical properties including high aqueous solubility. Optimization of the series has led to the discovery of 29, which has oral activity in a rat inflammatory pain model and limited brain exposure at analgesic doses, consistent with a lower risk of CNS-mediated tolerability issues.

Abstract 5598: KX02, a novel therapeutic for glioma

Abstract Objectives: Over 20,000 new cases of primary malignant brain tumors are diagnosed each year in the United States. Even with aggressive therapy 13,000 deaths are estimated to be attributed to these tumors. Few therapeutic agents are capable of effectively penetrating the blood-brain barrier. Fewer still are capable of selective molecular targeting. KX02 (Kinex Pharmaceuticals) is a synthetic, orally bioavailable, novel small molecule microtubule polymerization inhibitor with very high CNS penetration. In this study the efficacy of KX02 as a novel anti-cancer agent was tested directly using a mouse model of malignant glioma. Methodology & Results: The orthotopic GL261 glioma model in immune-competent, syngeneic C57BL/6 mice was used to evaluate KX02. Mice implanted intracerebrally with 1×105 GL261 cells treated with vehicle alone (saline) have a median survival time (MeST) of 21 days (range 18-28). Mice treated by oral KX02 (30 mg/kg, b.i.d.) have a MeST of 30.5 days ranging 23-32 days. In contrast, when KX02 is given orally at (30mg/kg, s.i.d.) the MeST increases to over 120 days, with more than 60% of the treatment group still alive 12 months later (p<0.0001). Specimens from these mice also showed lymphocytic infiltration of the tumor site. Further experiments were performed using immunocompromised mice (lacking functional T and B cells) on a C57BL/6 genetic background (B6.CB17-Prkdcscid/SzJ). These immunocompromised (SCID) mice bearing GL261 intracerebral tumors and treated with vehicle alone had a similar survival as the immune-competent C57BL/6 counterpart, however mice treated with KX02 now only had a MeST of 40 days (range 29-75). Interestingly, immunocompromised mice surviving longer than 45 days all progressed to develop lethal GL261 gliomas (observed by MRI) shortly after drug was discontinued. Long term survivor C57BL/6 mice from the immune-competent group also subsequently rejected a second GL261 tumor implant challenge, consistent with generation of productive immune memory. Additional molecular studies using cultured GL261 cells show that KX02 increased expression and altered the localization of intracellular survivin, a molecule that can be targeted by immunotherapy. Conclusions: The results of five independent studies indicate that KX02 slows the growth rate of intracerebral GL261 glioma relative to control groups. When given as a single dose per day (s.i.d.) KX02 led to complete tumor regression in up to 60% of treated mice without further progression. The subsequent rejection of a second tumor in these mice is indicative of immune memory. This magnitude of anti-tumor effect was not observed in the immunocompromised mice, suggesting that the once-daily dosing regimen with KX02 permits the generation of an effective immune response that contributes to long-term cures. Based on these data, further study of KX02, specifically in the treatment of brain cancer is clearly warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5598.

Discovery of 1-[4-(3-Chlorophenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridin-7-yl]-1-morpholin-4-ylmethanone (GSK554418A), a Brain Penetrant 5-Azaindole CB2 Agonist for the Treatment of Chronic Pain

We report the synthesis and SAR of a series of novel azaindole CB(2) agonists. 6-Azaindole 18 showed activity in an acute pain model but was inactive in a chronic model. 18 is a Pgp substrate with low brain penetration. The template was redesigned, and the resulting 5-azaindole 36 was a potent CB(2) agonist with high CNS penetration. This compound was efficacious in the acute model and the chronic joint pain model.

A double‐blind, randomized, placebo‐controlled, single‐dose study of the cyclooxygenase‐2 inhibitor, GW406381, as a treatment for acute migraine

The objective of the present study was to explore the clinical efficacy and tolerability of GW406381, a cyclooxygenase-2 (COX-2) inhibitor with relatively high CNS penetration, in acute migraine. This was a double-blind, single-dose study of GW406381 compared with placebo and naproxen sodium compared with placebo (protocol number CXA20008). Three hundred and thirty-seven subjects were randomized 1:1:1 to GW406381 (70 mg), naproxen sodium (825 mg), or placebo for the treatment of one migraine headache of moderate or severe intensity in a potential 8-week period. The primary end-point was the proportion of subjects with headache relief [reduction in headache severity score from pre-dose 2 (moderate) or 3 (severe) to 0 (no pain) or 1 (mild)] at 2 h post-dose for GW406381 compared with placebo. Significantly higher proportions of subjects treated with GW406381 (50%, P = 0.032) or naproxen sodium (56%, P = 0.005) than with placebo (35%) reported headache relief at 2 h post-dose. Additional significant benefits were observed on many secondary outcomes, including proportions of subjects pain-free, for both GW406381 and naproxen sodium treatment compared with placebo. Both active treatments were well tolerated. Single-dose GW406381 (70 mg) and naproxen sodium (825 mg) were effective and well tolerated in the treatment of acute migraine.

4-[6-(2-Aminoethyl)naphthalen-2-yl]benzonitriles are potent histamine H 3 receptor antagonists with high CNS penetration

4-[6-(2-Tertiaryaminoethyl)naphthalen-2-yl]benzonitriles are conformationally constrained histamine H 3 receptor antagonists with high potency and selectivity. The analogs were designed around a naphthalene core, with the goal of enhancing lipophilicity and CNS penetration, as compared to a previously reported benzofuran series. The SAR of the tertiary amine moiety is similar to that reported for the benzofuran series, with analogs bearing a 2-methylpyrrolidine substituent possessing the greatest rat and human H 3 receptor binding affinities.

Steady-State Brain Concentrations of Antihistamines in Rats

The purpose of this study was to measure the in vivo brain distribution of antihistamines and assess the influence of in vitro permeability, P-glycoprotein (Pgp) efflux, and plasma protein binding. Six antihistamines (acrivastine, chlorpheniramine, diphenhydramine doxylamine, fexofenadine, terfenadine) were selected based on previously reported in vitro permeability and Pgp efflux properties and dosed intravenously to steady-state plasma concentrations of 2–10 µmol/l in rats. Plasma and brain concentrations were measured by LC/MS/MS, and protein binding determined by ultrafiltration. Doxylamine, diphenhydramine and chlorpheniramine had brain-to-plasma concentration ratios of 4.34 ± 1.26, 18.4 ± 2.35 and 34.0 ± 9.02, respectively. These drugs had high passive membrane permeability (>310 nm/s), moderate protein binding (71–84%) and were not Pgp substrates; features that yield high CNS penetration. In contrast, acrivastine and fexofenadine had low brain-to-plasma ratios of 0.072 ± 0.014 and 0.018 + 0.002, consistent with low passive membrane permeability for both compounds (16.2 and 66 nm/s, respectively) and Pgp efflux. Finally, terfenadine had a brain-to-plasma ratio of 2.21 ± 1.00 even though it underwent Pgp-mediated efflux (in vitro ratio = 2.88). Terfenadine’s high passive permeability (285 nm/s) overcame the Pgp-mediated efflux to yield brain-to-plasma ratio >1. The brain-to-unbound plasma ratio was 22-fold higher suggesting that protein binding (96.3% bound) limited terfenadine’s brain distribution. In conclusion, passive membrane permeability, Pgp-mediated efflux and/or high plasma protein binding influence the in vivo brain distribution of antihistamine drugs.

Design and synthesis of trans-N-[4-[2-(6-cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (SB-277011): A potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and CNS penetration in the rat.

A selective dopamine D(3) receptor antagonist offers the potential for an effective antipsychotic therapy, free of the serious side effects of currently available drugs. Using clearance and brain penetration studies as a screen, a series of 1,2,3, 4-tetrahydroisoquinolines, exemplified by 13, was identified with high D(3) affinity and selectivity against the D(2) receptor. Following examination of molecular models, the flexible butyl linker present in 13 was replaced by a more conformationally constrained cyclohexylethyl linker, leading to compounds with improved oral bioavailability and selectivity over other receptors. Subsequent optimization of this new series to improve the cytochrome P450 inhibitory profile and CNS penetration gave trans-N-[4-[2-(6-cyano-1, 2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarbo xamide (24, SB-277011). This compound is a potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and brain penetration in the rat and represents an excellent new chemical tool for the investigation of the role of the dopamine D(3) receptor in the CNS.