ABSTRACT
We report the investigation of sulfonamide-derived Cav2.2 inhibitors to address drug-metabolism liabilities with this lead class of analgesics. Modification of the benzamide substituent provided improvements in both potency and selectivity. However, we discovered that formation of the persistent 3-(trifluoromethyl)benzenesulfonamide metabolite was an endemic problem in the sulfonamide series and that the replacement of the center aminopiperidine scaffold failed to prevent this metabolic pathway. This issue was eventually addressed by application of a bioisostere strategy. The new gem-dimethyl sulfone series retained Cav2.2 potency without the liability of the circulating sulfonamide metabolite.
ABSTRACT
The voltage-gated calcium channel Ca(v)2.2 (N-type calcium channel) is a critical regulator of synaptic transmission and has emerged as an attractive target for the treatment of chronic pain. We report here the discovery of sulfonamide-derived, state-dependent inhibitors of Ca(v)2.2. In particular, 19 is an inhibitor of Ca(v)2.2 that is selective over cardiac ion channels, with a good preclinical PK and biodistribution profile. This compound exhibits dose-dependent efficacy in preclinical models of inflammatory hyperalgesia and neuropathic allodynia and is devoid of ancillary cardiovascular or CNS pharmacology at the doses tested. Importantly, 19 exhibited no efficacy in Ca(v)2.2 gene-deleted mice. The discovery of metabolite 26 confounds further development of members of this aminopiperidine sulfonamide series. This discovery also suggests specific structural liabilities of this class of compounds that must be addressed.
Subject(s)
Calcium Channel Blockers/pharmacology , Calcium Channels, N-Type/chemistry , Calcium Channels, N-Type/physiology , Chronic Pain/drug therapy , Hyperalgesia/drug therapy , Inflammation/drug therapy , Neuralgia/drug therapy , Piperidines/pharmacology , Sulfonamides/pharmacology , Animals , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/pharmacokinetics , Calcium Channels, N-Type/metabolism , Cells, Cultured , Dogs , Humans , Mice , Mice, Knockout , Microsomes, Liver/drug effects , Patch-Clamp Techniques , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokinetics , Tissue DistributionABSTRACT
Long chain L-2-hydroxy acid oxidase 2 (Hao2) is a peroxisomal enzyme expressed in the kidney and the liver. Hao2 was identified as a candidate gene for blood pressure (BP) quantitative trait locus (QTL) but the identity of its physiological substrate and its role in vivo remains largely unknown. To define a pharmacological role of this gene product, we report the development of selective inhibitors of Hao2. We identified pyrazole carboxylic acid hits 1 and 2 from screening of a compound library. Lead optimization of these hits led to the discovery of 15-XV and 15-XXXII as potent and selective inhibitors of rat Hao2. This report details the structure activity relationship of the pyrazole carboxylic acids as specific inhibitors of Hao2.
Subject(s)
Alcohol Oxidoreductases/antagonists & inhibitors , Carboxylic Acids/chemistry , Enzyme Inhibitors/chemistry , Pyrazoles/chemistry , Thiophenes/chemistry , Alcohol Oxidoreductases/metabolism , Animals , Binding Sites , Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacokinetics , Computer Simulation , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Humans , Kidney/enzymology , Kidney/metabolism , Liver/enzymology , Liver/metabolism , Protein Structure, Tertiary , Pyrazoles/chemical synthesis , Pyrazoles/therapeutic use , Rats , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/therapeutic useABSTRACT
GPR91, a 7TM G-Protein-Coupled Receptor, has been recently deorphanized with succinic acid as its endogenous ligand. Current literature indicates that GPR91 plays role in various pathophysiology including renal hypertension, autoimmune disease and retinal angiogenesis. Starting from a small molecule high-throughput screening hit 1 (hGPR91 IC(50): 0.8 µM)-originally synthesized in Merck for Bradykinin B(1) Receptor (BK(1)R) program, systematic structure-activity relationship study led us to discover potent and selective hGPR91 antagonists e.g. 2c, 4c, and 5 g (IC(50): 7-35 nM; >1000 fold selective against hGPR99, a closest related GPCR; >100 fold selective in Drug Matrix screening). This initial work also led to identification of two structurally distinct and orally bio-available lead compounds: 5g (%F: 26) and 7e (IC(50): 180 nM; >100 fold selective against hGPR99; %F: 87). A rat pharmacodynamic assay was developed to characterize the antagonists in vivo using succinate induced increase in blood pressure. Using two representative antagonists, 2c and 4c, the GPR91 target engagement was subsequently demonstrated using the designed pharmacodynamic assay.
Subject(s)
Drug Discovery , Receptors, G-Protein-Coupled/antagonists & inhibitors , Small Molecule Libraries/chemical synthesis , Administration, Oral , Animals , Inhibitory Concentration 50 , Male , Molecular Structure , Rats , Rats, Wistar , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacologyABSTRACT
N-type calcium channels (Ca(v)2.2) have been shown to play a critical role in pain. A series of low molecular weight 2-aryl indoles were identified as potent Ca(v)2.2 blockers with good in vitro and in vivo potency.
Subject(s)
Calcium Channel Blockers/therapeutic use , Calcium Channels, N-Type/metabolism , Indoles/therapeutic use , Pain/drug therapy , Animals , Calcium Channel Blockers/pharmacokinetics , Calcium Channel Blockers/pharmacology , Dogs , Haplorhini , Humans , Indoles/pharmacokinetics , Indoles/pharmacology , RatsABSTRACT
l-2-Hydroxy acid oxidase (Hao2) is a peroxisomal enzyme with predominant expression in the liver and kidney. Hao2 was recently identified as a candidate gene for blood pressure quantitative trait locus in rats. To investigate a pharmacological role of Hao2 in the management of blood pressure, selective Hao2 inhibitors were developed. Optimization of screening hits 1 and 2 led to the discovery of compounds 3 and 4 as potent and selective rat Hao2 inhibitors with pharmacokinetic properties suitable for in vivo studies in rats. Treatment with compound 3 or 4 resulted in a significant reduction or attenuation of blood pressure in an established or developing model of hypertension, deoxycorticosterone acetate-treated rats. This is the first report demonstrating a pharmacological benefit of selective Hao2 inhibitors in a relevant model of hypertension.
ABSTRACT
A series of novel biphenyl pyrazole dicarboxamides were identified as potential sodium channel blockers for treatment of neuropathic pain. Compound 20 had outstanding efficacy in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain.
Subject(s)
Biphenyl Compounds/chemistry , Neuralgia/drug therapy , Pyrazoles/chemistry , Sodium Channel Blockers/chemistry , Sodium Channels/chemistry , Animals , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/therapeutic use , Dogs , Drug Evaluation, Preclinical , Humans , Mice , Microsomes, Liver/metabolism , Motor Activity/drug effects , Pyrazoles/pharmacokinetics , Pyrazoles/therapeutic use , Rats , Sodium Channel Blockers/pharmacokinetics , Sodium Channel Blockers/therapeutic use , Sodium Channels/metabolismABSTRACT
Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. A series of low molecular weight biaryl substituted pyrazole carboxamides were identified with good in-vitro potency and in-vivo efficacy. Compound 26, a Nav1.7 blocker has excellent efficacy in the Chung model of neuropathic pain.
Subject(s)
Neuralgia/drug therapy , Pyrazoles/chemistry , Pyrazoles/therapeutic use , Sodium Channel Blockers/chemistry , Sodium Channel Blockers/therapeutic use , Sodium Channels/metabolism , Animals , Dogs , Haplorhini , Humans , Microsomes, Liver/metabolism , NAV1.7 Voltage-Gated Sodium Channel , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Sodium Channel Blockers/pharmacokinetics , Sodium Channel Blockers/pharmacology , Structure-Activity RelationshipABSTRACT
Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. With a goal to develop potent peripherally active sodium channel blockers, a series of low molecular weight biaryl substituted imidazoles, oxazoles, and thiazole carboxamides were identified with good in vitro and in vivo potency.
Subject(s)
Neuralgia/drug therapy , Oxazoles/therapeutic use , Sodium Channel Blockers/therapeutic use , Sodium Channels/metabolism , Thiazoles/therapeutic use , Animals , Dogs , Humans , Imidazoles/chemistry , Imidazoles/metabolism , Imidazoles/pharmacology , Imidazoles/therapeutic use , Microsomes, Liver/metabolism , NAV1.7 Voltage-Gated Sodium Channel , Oxazoles/chemistry , Oxazoles/metabolism , Oxazoles/pharmacology , Rats , Sodium Channel Blockers/chemistry , Sodium Channel Blockers/metabolism , Sodium Channel Blockers/pharmacology , Thiazoles/chemistry , Thiazoles/metabolism , Thiazoles/pharmacologyABSTRACT
We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we postulate that the SHI-1:2 extend the existing HDAC inhibitor pharmacophore to include an internal binding domain.
Subject(s)
Benzene Derivatives/chemical synthesis , Benzene Derivatives/pharmacology , Histone Deacetylase Inhibitors , Models, Molecular , Benzene Derivatives/chemistry , Binding Sites/drug effects , Histone Deacetylase 1 , Histone Deacetylase 2 , Histone Deacetylases/chemistry , Histone Deacetylases/metabolism , Humans , Molecular Structure , Protein Isoforms , Repressor Proteins , Structure-Activity RelationshipABSTRACT
Histone deacetylase (HDAC) inhibitors offer a promising strategy for cancer therapy and the first generation HDAC inhibitors are currently in clinical trials. A structurally novel series of HDAC inhibitors based on the natural cyclic tetrapeptide Apicidin is described. Selected screening of the sample collection looking for L-2-amino-8-oxodecanoic acid (L-Aoda) derivatives identified a small acyclic lead molecule 1 with the unusual ketone zinc binding group. SAR studies around this lead resulted in optimization to potent, low molecular weight, selective, non-hydroxamic acid HDAC inhibitors, equipotent to current clinical candidates.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Amides/chemistry , Amino Acids/chemistry , Cell Line , Enzyme Inhibitors/classification , Histone Deacetylases/metabolism , Humans , Indoles/chemistry , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Molecular Structure , Sensitivity and Specificity , Structure-Activity RelationshipABSTRACT
Efficient routes to access the 2", 3", 4", and 6" registers of the nodulisporic acid (NsA) side chain are disclosed. A mild one-carbon, Ph(2)CdoublebondNCH(2)CtriplebondN mediated homologation of NsA's 3"-aldehyde permitted access to the 4"-register. Curtius reaction of NsA's 3"-acid yielded the corresponding 2"-aldehyde 4 from which the unnatural Delta(2",3")-olefin isomer 2b was obtained. In addition, Arndt-Eistert reactions of the parent NsA permitted a one-carbon homologation to the 6" register. These efforts identified new analogues with significant flea activity and illustrated the biological significance of unsaturation at the 1",2" register.
Subject(s)
Indoles/chemistry , Insecticides/chemical synthesis , Alkenes , Animals , Dose-Response Relationship, Drug , Indoles/pharmacology , Insecticides/pharmacology , Siphonaptera/drug effects , Structure-Activity RelationshipABSTRACT
A series of new, diene-modified nodulisporic acid analogues (2) bearing diverse functionality at the 3"- and 4"-sites was efficiently prepared from the 3"-aldehyde 3. Biological evaluation of these synthetic nodulisporic acid analogues for systemic flea efficacy identified potent compounds and further clarified the structural requirements for ectoparasite activity.
Subject(s)
Indoles/chemical synthesis , Insecticides/chemical synthesis , Animals , Cattle , Ectoparasitic Infestations/drug therapy , Indoles/chemistry , Insecticides/chemistry , Siphonaptera , Stereoisomerism , Structure-Activity RelationshipABSTRACT
An efficient synthesis of the truncated 3"-aldehyde (3) from nodulisporic acid A (1) under mild conditions is described. Further oxidation of 3 to 3"-carboxylic acid (4) and its subsequent oxidative degradation produced 1"-aldehyde (5). These new derivatives are versatile intermediates for the preparation of new, side chain modified derivatives of nodulisporic acid A. [reaction: see text]