Stability of antibody–drug conjugates (ADCs) in mouse serum is one of the critical requirements for the evaluation of ADCs in mouse tumor models. Described herein is a strategy to address the mouse ...serum instability of uncialamycin linker–payloads through various chemical approaches that involve modification of different parts of the linker and payload. This effort ultimately led to the identification of a m-amide p-aminobenzyl carbamate (MA-PABC) group that resulted in linkers with dramatic improvement of mouse serum stability without affecting the desired proteolytic cleavage.
Agonists at the nicotinic acetylcholine alpha 7 receptor (nAChR α7) subtype have the potential to treat cognitive deficits in patients with Alzheimer's disease (AD) or schizophrenia. Visuo-spatial ...paired associates learning (vsPAL) is a task that has been shown to reliably predict conversion from mild cognitive impairment to AD in humans and can also be performed by nonhuman primates. Reversal of scopolamine-induced impairment of vsPAL performance may represent a translational approach for the development of nAChR α7 agonists. The present study investigated the effect of treatment with the acetylcholinesterase inhibitor, donepezil, or three nAChR α7 agonists, BMS-933043, EVP-6124 and RG3487, on vsPAL performance in scopolamine-treated cynomolgus monkeys. Scopolamine administration impaired vsPAL performance accuracy in a dose- and difficulty- dependent manner. The impairment of eventual accuracy, a measure of visuo-spatial learning during the task, was significantly ameliorated by treatment with donepezil (0.3 mg/kg, i.m.), EVP-6124 (0.01 mg/kg, i.m.) or BMS-933043 (0.03, 0.1 and 0.3 mg/kg, i.m.). Both nAChR α7 agonists showed inverted-U shaped dose-effect relationships with EVP-6124 effective at a single dose only whereas BMS-933043 was effective across at least a 10 fold dose/exposure range. RG3487 was not efficacious in this paradigm at the dose range examined (0.03-1 mg/kg, i.m.). These results are the first demonstration that the nAChR α7 agonists, EVP-6124 and BMS-933043, can ameliorate scopolamine-induced cognitive deficits in nonhuman primates performing the vsPAL task.
The antidepressant activity of the N-methyl-D-aspartate (NMDA) receptor channel blocker, ketamine, has led to the investigation of negative allosteric modulators (NAMs) selective for the NR2B ...receptor subtype. The clinical development of NR2B NAMs would benefit from a translational pharmacodynamic biomarker that demonstrates brain penetration and functional inhibition of NR2B receptors in preclinical species and humans. Quantitative electroencephalography (qEEG) is a translational measure that can be used to demonstrate pharmacodynamic effects across species. NMDA receptor channel blockers, such as ketamine and phencyclidine, increase the EEG gamma power band, which has been used as a pharmacodynamic biomarker in the development of NMDA receptor antagonists. However, detailed qEEG studies with ketamine or NR2B NAMs are lacking in nonhuman primates. The aim of the present study was to determine the effects on the qEEG power spectra of the NR2B NAMs traxoprodil (CP-101,606) and BMT-108908 in nonhuman primates, and to compare them to the NMDA receptor channel blockers, ketamine and lanicemine. Cynomolgus monkeys were surgically implanted with EEG radio-telemetry transmitters, and qEEG was measured after vehicle or drug administration. The relative power for a number of frequency bands was determined. Ketamine and lanicemine increased relative gamma power, whereas the NR2B NAMs traxoprodil and BMT-108908 had no effect. Robust decreases in beta power were elicited by ketamine, traxoprodil and BMT-108908; and these agents also produced decreases in alpha power and increases in delta power at the doses tested. These results suggest that measurement of power spectra in the beta and delta bands may represent a translational pharmacodynamic biomarker to demonstrate functional effects of NR2B NAMs. The results of these studies may help guide the selection of qEEG measures that can be incorporated into early clinical evaluation of NR2B NAMs in healthy humans.
The development of alpha7 nicotinic acetylcholine receptor agonists is considered a promising approach for the treatment of cognitive symptoms in schizophrenia patients. In the present studies we ...characterized the novel agent, (2R)-N-(6-(1H-imidazol-1-yl)-4-pyrimidinyl)-4'H-spiro4-azabicyclo2.2.2octane-2,5'-1,3oxazol-2'-amine (BMS-933043), in vitro and in rodent models of schizophrenia-like deficits in cognition and sensory processing. BMS-933043 showed potent binding affinity to native rat (Ki = 3.3 nM) and recombinant human alpha7 nicotinic acetylcholine receptors (Ki = 8.1 nM) and agonist activity in a calcium fluorescence assay (EC50 = 23.4 nM) and whole cell voltage clamp electrophysiology (EC50 = 0.14 micromolar (rat) and 0.29 micromolar (human)). BMS-933043 exhibited a partial agonist profile relative to acetylcholine; the relative efficacy for net charge crossing the cell membrane was 67% and 78% at rat and human alpha7 nicotinic acetylcholine receptors respectively. BMS-933043 showed no agonist or antagonist activity at other nicotinic acetylcholine receptor subtypes and was at least 300 fold weaker at binding to and antagonizing human 5-HT3A receptors (Ki = 2,451 nM; IC50 = 8,066 nM). BMS-933043 treatment i) improved 24 hour novel object recognition memory in mice (0.1-10 mg/kg, sc), ii) reversed MK-801-induced deficits in Y maze performance in mice (1-10 mg/kg, sc) and set shift performance in rats (1-10 mg/kg, po) and iii) reduced the number of trials required to complete the extradimensional shift discrimination in neonatal PCP treated rats performing the intra-dimensional/extradimensional set shifting task (0.1-3 mg/kg, po). BMS-933043 also improved auditory gating (0.56-3 mg/kg, sc) and mismatch negativity (0.03-3 mg/kg, sc) in rats treated with S(+)ketamine or neonatal phencyclidine respectively. Given this favorable preclinical profile BMS-933043 was selected for further development to support clinical evaluation in humans.
Monoclonal antibodies (mAb) directed to tumor-associated antigens (TAA) or antigens differentially expressed on the tumor vasculature have been covalently linked to drugs that have different ...mechanisms of action and various levels of potency. The use of these mAb immunoconjugates to selectively deliver drugs to tumors has the potential to both improve antitumor efficacy and reduce the systemic toxicity of therapy. Several immunoconjugates, particularly those that incorporate internalizing antibodies and tumor-selective linkers, have demonstrated impressive activity in preclinical models. Immunoconjugates that deliver doxorubicin, maytansine and calicheamicin are currently being evaluated in clinical trials. The feasibility of using immunoconjugates as cancer therapeutics has been clearly demonstrated. Gemtuzumab ozogamicin, a calicheamicin conjugate that targets CD33, has recently been approved by the Food and Drug Administration (FDA) for treatment of acute myelogenous leukemia (AML). This review concentrates on the properties of the tumor and the characteristics of the mAb, linker, and drugs that influence the efficacy, potency, and selectivity of immunconjugates selected for cancer treatment.
A series of amines with structure 10 were synthesized and tested for inhibition of the human serotonin transporter (hSERT).
A series of racemic 3-(trans-2-aminomethylcyclopentyl)indoles was ...synthesized and found to have potent binding to the human serotonin transporter (hSERT). The most active analog was synthesized stereospecifically and the active enantiomer was shown to have high affinity binding to hSERT.
A series of conformationally restricted homotryptamines has been synthesized and shown to be potent inhibitors of hSERT. Conformational restriction of the homotryptamine side chain was attained by ...the insertion of a cyclopentyl ring, with the indole ring and the terminal dialkylamino group occupying the 1- and 3-positions, respectively. Nitrile and fluoro substitutions at the indole 5-position gave highest hSERT potency. Preferred cyclopentane ring stereochemistry in both series was cis (1S,3R for 5-CN compound 8a, 1R,3S for 5-F compound 9a). High hSERT binding affinity was observed for 8a and 9a (0.22 and 0.63 nM, respectively). The corresponding trans isomers were 4−9 times less potent. 8a, dosed at 1 and 3 mg/kg po, produced a robust, dose-dependent increase in extracellular serotonin in the frontal cortex of rats, similar to that induced by paroxetine at 5 mg/kg, po. By contrast, 9a did not produce a significant increase in extracellular serotonin in rat frontal cortex at 3 mg/kg po due to relatively low brain and plasma levels.
Hybrid molecules containing the cyclopropylmethylamino side chain found in the parent homotryptamine system and an isosteric heteroaryl or naphthyl core were prepared and their binding affinities for ...the human serotonin transporter determined.
A series of hybrid molecules containing the cyclopropylmethylamino side chain found in homotryptamine (1
S,2
S)-
2c and an isosteric heteroaryl or naphthyl core were prepared and their binding affinities for the human serotonin transporter determined. The most potent isosteres were CN-substituted naphthalenes. These results demonstrate that isosteric aromatic cores which lack an H-bond donor site may be substituted for the indole nucleus without substantial loss in hSERT binding.
The synthesis of the highly potent and selective serotonin reuptake inhibitor 1 (BMS-594726) is described. In the key construction step, an enantioselective alkylation of the indole nucleus with an ...α-branched α,β-unsaturated aldehyde 7 was accomplished utilizing MacMillan's imidazolidinone catalyst 3b. A rationale is presented for the unexpected stereochemical result, as well as the novel reactivity of the α-branched substrate.
Bivalent doxorubicin (DOX)-dipeptides (
16a–
c) were prepared and conjugated to the monoclonal antibody BR96. The dipeptides are cleaved by lysosomal proteases following internalization of the ...resulting immunoconjugates. Conjugate
18b demonstrated antigen-specific in vitro tumor cell killing activity (IC
50=0.2
μM) that was equipotent to DOX with a near doubling of drug molecules/MAb. Size exclusion chromatography showed
18b to be a noncovalent dimer that was formed immediately upon conjugation.
BR96 immunoconjugates carrying 14 molecules of doxorubicin attached through bivalent, lysosomally-cleavable dipeptides linkers were prepared.
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