Mark R. Player

Discovery and SAR of novel Naphthyridines as potent inhibitors of spleen tyrosine kinase (SYK).

The discovery of novel 5,7-disubstituted[1,6]naphthyridines as potent inhibitors of Spleen Tyrosine Kinase (SYK) is discussed. The SAR reveals the necessity for a 7-aryl group with preference towards para substitution and that this in combination with 5-aminoalkylamino substituents further improved the potency of the compounds. The initial SAR as well as a survey of the other positions is discussed in detail.

Identification of Diaryl Ether-Based Ligands for Estrogen-Related Receptor α as Potential Antidiabetic Agents

Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of diaryl ether based thiazolidenediones, which function as selective ligands against this receptor. Series optimization provided several potent analogues that inhibit the recruitment of a coactivator peptide fragment in in vitro biochemical assays (IC(50) < 150 nM) and cellular two-hybrid reporter assays against the ligand binding domain (IC(50) = 1-5 μM). A cocrystal structure of the ligand-binding domain of ERRα with lead compound 29 revealed the presence of a covalent interaction between the protein and ligand, which has been shown to be reversible. In diet-induced murine models of obesity and in an overt diabetic rat model, oral administration of 29 normalized insulin and circulating triglyceride levels, improved insulin sensitivity, and was body weight neutral. This provides the first demonstration of functional activities of an ERRα ligand in metabolic animal models.

In vitro evaluation of a series of Azone analogs as dermal penetration enhancers. II. (Thio) amides

Abstract The sorption promoting ability of nine Azone ( N -dodecylazacycloheptan-2-one) analogs was tested against the model drug, hydrocortisone 21-acetate using a hairless mouse skin model in vitro. The synthesis of these compounds is presented. The enhancers were applied in propylene glycol, 1 h prior to the application of the steroid which was applied as a saturated suspension in the same vehicle. All but enhancers 3–5, 8 , and 9 were applied at 0.4 M. The remaining enhancers (all solids) were applied at their respective saturation solubilities. Flux, receptor concentrations, and skin accumulation of hydrocortisone acetate were measured over 24 h and compared with controls (no enhancer) and three model enhancers: Azone ( N -dodecylazacycloheptan-2-one), 2-pyrrolidinone, and N -methyl-2-pyrrolidinone. Pre-treatment of skin with the Azone analogs markedly increased penetration and skin retention of the steroid. The greatest enhancement of flux was observed for 2 , where flux increased 53.8-fold over control and 2.76-fold over Azone; receptor concentrations were 35.37-fold and skin retentions 1.6-fold higher than control. Compound 1 gave the greatest skin retention enhancement ratio (ER) (2.2 over control) of the series, while 2-pyrrolidinone produced an ER of 3.2, and Azone 1.5 compared with controls at an ER of 1.0.

Azone analogues as penetration enhancers: effect of different vehicles on hydrocortisone acetate skin permeation and retention

Abstract The permeation and skin retention of hydrocortisone-21 -acetate in hairless mouse skin in vitro was examined following topical pretreatment with four novel enhancers in four vehicles: isopropyl myristate (IPM), N-methyl-2-pyrrolidinone, (MP), polyethylene glycol 400 (PEG), and caprylic/capric/linoleic triglyceride (CT, Miglyol 818®). Controls included no vehicle pretreatment and vehicle pretreatment one hour prior to drug application to the skin. The standard enhancer studied was Azone. With enhancer 1 [N-(1-oxododecyl)morpholine], the rank order for 24 hour cumulative receptor steroid concentrations Q24 (μM) was PEG > IPM > MP/CT; for enhancer 2 [N-dodecyl-2-piperidinone]: PEG > IPM/MP/CT; for enhancer 3 [N-dodecyl-2-pyrrolidinone]: MP > CT/PEG/IPM; for enhancer 4 [N-(1-oxotetradecyl)hexahydro-2-oxo-1H-azepine]: PEG/MP/IPM > CT. For Q24 controls, one hour pretreatment with vehicles alone, rank order was IPM > MP/CT > PEG. Coadministration of the steroid with enhancer 2 with PEG or with propylene glycol reduced enhancer effectiveness compared to pretreatment with vehicle alone.

Pyrido[2,3-d]pyrimidin-5-ones: A Novel Class of Antiinflammatory Macrophage Colony-Stimulating Factor-1 Receptor Inhibitors†

A series of pyrido[2,3-d]pyrimidin-5-ones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). FMS inhibitors may be useful in treating rheumatoid arthritis and other chronic inflammatory diseases. Structure-based optimization of the lead amide analogue 10 led to hydroxamate analogue 37, which possessed excellent potency and an improved pharmacokinetic profile. During the chronic phase of streptococcal cell wall-induced arthritis in rats, compound 37 (10, 3, and 1 mg/kg) was highly effective at reversing established joint swelling. In an adjuvant-induced arthritis model in rats, 37 prevented joint swelling partially at 10 mg/kg. In this model, osteoclastogenesis and bone erosion were prevented by low doses (1 or 0.33 mg/kg) that had minimal impact on inflammation. These data underscore the potential of FMS inhibitors to prevent erosions and reduce symptoms in rheumatoid arthritis.

Discovery and clinical evaluation of 1-{N-[2-(amidinoaminooxy)ethyl]amino}carbonylmethyl-6-methyl-3-[2,2-difluoro-2-phenylethylamino]pyrazinone (RWJ-671818), a thrombin inhibitor with an oxyguanidine P1 motif.

We have identified RWJ-671818 (8) as a novel, low molecular weight, orally active inhibitor of human alpha-thrombin (K(i) = 1.3 nM) that is potentially useful for the acute and chronic treatment of venous and arterial thrombosis. In a rat deep venous thrombosis model used to assess antithrombotic efficacy, oral administration of 8 at 30 and 50 mg/kg reduced thrombus weight by 87 and 94%, respectively. In an anesthetized rat antithrombotic model, where electrical stimulation of the carotid artery created a thrombus, 8 prolonged occlusion time 2- and 3-fold at 0.1 and 1.0 mg/kg, i.v., respectively, and more than doubled activated clotting time and activated partial thromboplastin time at the higher dose. This compound had excellent oral bioavailability of 100% in dogs with an estimated half-life of approximately 3 h. On the basis of its noteworthy preclinical data, 8 was advanced into human clinical trials and successfully progressed through phase 1 studies.

Optimization of a Potent Class of Arylamide Colony-Stimulating Factor-1 Receptor Inhibitors Leading to Anti-inflammatory Clinical Candidate 4-Cyano-N-[2-(1-cyclohexen-1-yl)-4-[1-[(dimethylamino)acetyl]-4-piperidinyl]phenyl]-1H-imidazole-2-carboxamide (JNJ-28312141).

A class of potent inhibitors of colony-stimulating factor-1 receptor (CSF-1R or FMS), as exemplified by 8 and 21, was optimized to improve pharmacokinetic and pharmacodynamic properties and potential toxicological liabilities. Early stage absorption, distribution, metabolism, and excretion assays were employed to ensure the incorporation of druglike properties resulting in the selection of several compounds with good activity in a pharmacodynamic screening assay in mice. Further investigation, utilizing the type II collagen-induced arthritis model in mice, culminated in the selection of anti-inflammatory development candidate JNJ-28312141 (23, FMS IC(50) = 0.69 nM, cell assay IC(50) = 2.6 nM). Compound 23 also demonstrated efficacy in rat adjuvant and streptococcal cell wall-induced models of arthritis and has entered phase I clinical trials.

Benzo[d]imidazole Transient Receptor Potential Vanilloid 1 Antagonists for the Treatment of Pain: Discovery of trans-2-(2-{2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol (Mavatrep)

Reported herein is the design, synthesis, and pharmacologic characterization of a class of TRPV1 antagonists constructed on a benzo[d]imidazole platform that evolved from a biaryl amide lead. This design composes three sections: a 2-substituted 5-phenyl headgroup attached to the benzo[d]imidazole platform, which is tethered at the two position to a phenyl tail group. Optimization of this design led to the identification of 4 (mavatrep), comprising a trifluoromethyl-phenyl-vinyl tail. In a TRPV1 functional assay, using cells expressing recombinant human TRPV1 channels, 4 antagonized capsaicin-induced Ca(2+) influx, with an IC50 value of 4.6 nM. In the complete Freunds adjuvant- and carrageenan-induced thermal hypersensitivity models, 4 exhibited full efficacy, with ED80 values of 7.8 and 0.5 mg/kg, respectively, corresponding to plasma levels of 270.8 and 9.2 ng/mL, respectively. On the basis of its superior pharmacologic and safety profile, 4 (mavatrep) was selected for clinical development for the treatment of pain.

1,3-Oxazino[4,5-b]indole-2,4-(1H,9H)-diones and 5,6-dimethylpyrrolo-[2,3-d]-1,3-oxazin-2,4-(1H,7H)-diones as serine protease inhibitors

Abstract 9-Substituted-1,3-oxazino[4,5-b]indole-2,4-(1 H ,9 H )-diones and 7-substituted-5,6-dimethylpyrrolo[2,3-d]-1,3-oxazin-2,4-(1 H ,7 H )-diones are synthesized from indolo- or pyrrolo-β-enamino t -butyl esters in moderate yield. Certain compounds are found to inhibit human leukocyte elastase (HLE) and chymotrypsin selectively.

Investigation of enhancer structure activity relationships in congeners of 2-(1-nonyl)-1,3-dioxolane

AbstractTwelve analogues of 2-(1-nonyl)-1,3-dioxolane were examined for enhancer activity using occluded hairless mouse skin in vitro with hydrocortisone as the model drug. Controls consisted of no enhancer or vehicle pretreatment (I) or propylene glycol pretreatment 1 h prior to drug application (II). Enhancers were applied at 0.4 M in propylene glycol (PG) 1 h prior to skin application of a saturated suspension of hydrocortisone in the same vehicle. The highest 24-h receptor concentration (Q24) of steroid was observed using 2-(1-nonyl)-1,3-dioxolane: 131.472 ± 20.659 μM compared to Control I of 16.462 ± 4.859 Rm. Control II Q24 values were 34.015 ± 9.959 μm. The highest skin steroid content was produced by 2-(1-nonyl)-2-methyl-1,3-dioxolane: 431.4 ± 212.2 μg g-1 and 2-(1-nonyl)-2,4-dimethyl-1,3-dioxolane: 385.7 ± 138.7 μg g-1. Skin steroid content of Control I was 490.2 ± 243.2 μg g-1 and of II was 112.7 ± 31.3 μg g-1. Control I and II results indicated that PG was exhibiting enhancer activity. All 12 d...