Enzymatic Late-Stage Oxidation of Lead Compounds with Solubilizing Biomimetic Docking/Protecting groups.

Late-stage functionalization of lead compounds is of high interest in drug discovery since it offers an easy access to metabolites and derivatives of a lead compound without the need to redesign an often long multistep synthesis. Owing to their high degree of chemoselectivity, biocatalytic transformations, enzymatic oxidations in particular, are potentially very powerful because they could allow the synthesis of less lipophilic derivatives of a lead compound. In the majority of cases, enzymatic oxidations have been used in an empirical way as their regioselectivity is difficult to predict. In this publication, the concept of using docking/protecting groups in a biomimetic fashion was investigated, which could help steer the regioselectivity of a P450BM3 -mediated oxidation. A novel set of docking/protecting groups was designed that can be cleaved under very mild conditions and address the often problematic aqueous solubility of the substrates. Vabicaserin was used as tool compound containing typical groups such as basic, aliphatic, and aromatic moieties. The results were rationalized with the help of in silico docking and molecular dynamic studies.

Mitigating the Metabolic Liability of Carbonyl Reduction: Novel Calpain Inhibitors with P1' Extension.

Dysregulation of calpains 1 and 2 has been implicated in a variety of pathological disorders including ischemia/reperfusion injuries, kidney diseases, cataract formation, and neurodegenerative diseases such as Alzheimer's disease (AD). 2-(3-Phenyl-1H)-pyrazol-1-yl)nicotinamides represent a series of novel and potent calpain inhibitors with high selectivity and in vivo efficacy. However, carbonyl reduction leading to the formation of the inactive hydroxyamide was identified as major metabolic liability in monkey and human, a pathway not reflected by routine absorption, distribution, metabolism, and excretion (ADME) assays. Using cytosolic clearance as a tailored in vitro ADME assay coupled with in vitro hepatocyte metabolism enabled the identification of analogues with enhanced stability against carbonyl reduction. These efforts led to the identification of P1' modified calpain inhibitors with significantly improved pharmacokinetic profile including P1' N-methoxyamide 23 as potential candidate compound for non-central nervous system indications.

High-throughput quantitative and qualitative analysis of microsomal incubations by cocktail analysis with an ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometer system.

BACKGROUND: Metabolite identification studies are very resource intensive and also are rarely performed in early discovery. Here, we report the validation of an ultraperformance liquid chromatography-high-resolution mass spectrometry (UPLC-HRMS) platform for generating high-throughput stability data with structure elucidation in a single injection. MATERIALS & METHODS: Tandem mass spectrometry spectra were obtained for quantitative analysis using a generic information-dependent acquisition method from pooled microsomal samples incubated at low compound concentrations. RESULTS: A good correlation was observed between clearance determined using UPLC-HRMS and UPLC-triple-quadrupole analysis. Structural elucidation performed with MassMetaSite™ (Molecular Discovery, Perugia, Italy) software identified 85% of the major metabolites of eight marketed drugs and over 100 internal compounds under these conditions. CONCLUSION: For the first time, a high-throughput quantitative-qualitative workflow was established using a cocktail approach for sample analysis with UPLC-HRMS in order to enable metabolite identification in early discovery projects.

Potent and selective oxindole-based vasopressin 1b receptor antagonists with improved pharmacokinetic properties.

Herein we report the discovery of a novel series of vasopressin 1b (V1b) receptor antagonists, starting from potent but metabolically labile oxindole SSR149415. Masking the proline N,N-dimethyl amide moiety as an oxazole and attaching a benzylic amine moiety to the northern phenyl ring resulted in potent and selective V1b receptor antagonists with improved metabolic stability and improved pharmacokinetic properties in rat. Compound 18c was found to be efficacious in a rat model of anti-depressant activity.

Design and synthesis of novel potent and selective integrin alphanubeta3 antagonists--novel synthetic routes to isoquinolinone, benzoxazinone, and quinazolinone acetates.

An unexpected ring contraction of benzazepinone based alpha(nu)beta(3) antagonists led to the design of quinolinone-type derivatives. Novel and efficient synthetic routes to isoquinolinone, benzoxazinone, and quinazolinone acetates were established. Nanomolar alpha(nu)beta(3) antagonists based on these new scaffolds were prepared. Moreover, benzoxazinones 15a and 15b exhibited high microsomal stability and good permeability.

Synthesis and SAR of highly potent and selective dopamine D3-receptor antagonists: variations on the 1H-pyrimidin-2-one theme.

In our efforts to further pursue one of the most selective dopamine D(3)-receptor antagonists reported to date, we now describe the synthesis and SAR of novel and highly selective dopamine D(3) antagonists based on a 1H-pyridin-2-one or on a urea scaffold. The most potent compounds exhibited K(i) values toward the D(3) receptor in the nano- to subnanomolar range and high selectivity versus the related D(2) dopamine receptor. Thus, 1H-pyridin-2-one 7b displays oral bioavailability (F=37%) as well as brain penetration (brain plasma ratio 3.7) in rat. Within the urea series, an excellent D(3) versus D(2) selectivity (>100-fold) could be achieved by removal of one NH group (compound 6), although bioavailability (rat) was suboptimal (F<10%). These data significantly enhance our understanding of the D(3) pharmacophore and are expected to lead to novel approaches for the treatment of schizophrenia.

Synthesis and SAR of highly potent and selective dopamine D(3)-receptor antagonists: 1H-pyrimidin-2-one derivatives.

The synthesis and SAR of novel highly potent and selective dopamine D(3)-receptor antagonists based on a 1H-pyrimidin-2-one scaffold are described. A-690344 antagonized PD 128907-induced huddling deficits in rat (ED(50) 6.1mg/kg po), a social interaction paradigm.

Synthesis and SAR of highly potent and selective dopamine D(3)-receptor antagonists: Quinolin(di)one and benzazepin(di)one derivatives. herve.geneste@abbott.com.

The synthesis and SAR of novel and selective dopamine D(3)-receptor antagonists based on a 3,4-dihydro-1H-quinolin-2-one, a 1,3,4,5-tetrahydro-benzo[b]azepin-2-one, 1H-quinoline-2,4-dione or a 3,4-dihydro-1H-benzo[b]azepine-2,5-dione scaffold are discussed. A706149 (2.15mg/kg, po) antagonizes PD 128907-induced huddling deficits in rat, a social interaction paradigm.

Design and synthesis of 1,5- and 2,5-substituted tetrahydrobenzazepinones as novel potent and selective integrin alphaVbeta3 antagonists.

The design and synthesis of novel integrin alpha(V)beta(3) antagonists based on a 1,5- or 2,5-substituted tetrahydrobenzaezpinone core is described. In vitro activity of respective compounds was determined via alpha(V)beta(3) binding assay, and selected derivatives were submitted to further characterization in functional cellular assays. SAR was obtained by modification of the benzazepinone core, variation of the spacer linking guanidine moiety and core, and modification of the guanidine mimetic. These efforts led to the identification of novel alpha(V)beta(3) inhibitors displaying potency in the subnanomolar range, selectivity versus alpha(IIb)beta(3) and functional efficacy in relevant cellular assays. A method for the preparation of enantiomerically pure derivatives was developed, and respective enantiomers evaluated in vitro. Compounds 31 and 37 were assessed for metabolic stability, resorption in the Caco-2 assay and pharmacokinetics.

Highly potent and selective alphaVbeta3-receptor antagonists: solid-phase synthesis and SAR of 1-substituted 4-amino-1H-pyrimidin-2-ones.

Solid-phase synthesis and SAR of alpha(V)beta(3)-receptor antagonists based on a N(1)-substituted 4-amino-1H-pyrimidin-2-one scaffold are described. The most potent compounds exhibited IC(50) values towards alpha(V)beta(3) in the nano- to subnanomolar range and high selectivity versus related integrins like alpha(IIb)beta(3). For selected examples efficacy in functional cellular assays was demonstrated.

Synthesis of highly potent and selective hetaryl ureas as integrin alpha(V)beta3-receptor antagonists.

Solid-phase synthesis and SAR of integrin alpha(V)beta3-receptor antagonists containing a urea moiety as non-basic guanidine mimetic are described. The most potent compounds exhibited IC(50) values towards alpha(V)beta3 in the nanomolar range and high selectivity versus related integrins like alpha(IIb)beta3. For selected examples efficacy in functional cellular assays is demonstrated.

Synthesis and SAR of N-substituted dibenzazepinone derivatives as novel potent and selective alpha(V)beta(3) antagonists.

Synthesis and SARs of new integrin alpha(V)beta(3) antagonists based on an N-substituted dibenzazepinone scaffold are described. Variation of spacer and guanidine mimetic led to potent compounds exhibiting an IC(50) towards alpha(V)beta(3) in the nanomolar range, high selectivity versus integrin alpha(IIb)beta(3) and efficacy in functional cellular assays.