Heteroleptic ruthenium bis-terpyridine complexes bearing a 4-(dimethylamino)phenyl donor and free coordination sites for hydrogen photo-evolution.

Motivated by the recent report of a heteroleptic ruthenium bis-terpyridine complex [Ru(toltpy)(bipytpy)](PF6)2 (toltpy: 4'-(tolyl)-2,2':6',2''-terpyridine; bipytpy: 4'-(4-bromophenyl)-4,4''':4'',4''''-di-pyridinyl-2,2':6',2''-terpyridine) capable of driving the photo-evolution of hydrogen with a constant rate of activity for 12 days [M. Rupp et al., Inorg. Chem., 2019, 58, 9127-9134], we investigated the impact of an internal electron donor on the photoactivity of three new ruthenium bis-terpyridine photosensitizers. We used 4'-(N,N-dimethylaminophenyl)-4,4''-di-tert-butyl-2,2':6',2''-terpyridine (Dtpy) as the donor ligand. These complexes also bear peripheral coordination sites at various positions on the terpyridine backbone, allowing for photosensitizer-catalyst interactions. Their performances in photocatalysis under blue and green light (450 and 525 nm, respectively) were measured, in the presence of triethanolamine, using a cobaloxime catalyst [Co(dmgH)2(H2O)2](BF4)2. Complexes C1[Ru(Dtpy)(pytpy)](PF6)2 (pytpy: 4'-(pyridin-4-yl)-2,2':6',2''-terpyridine) and C3[Ru(Dtpy)(bipytpy)](PF6)2 appeared to have a photostability similar to that of [Ru(toltpy)(bipytpy)](PF6)2 but with lower activity rates, while C2[Ru(Dtpy)(pz2bpy)](PF6)2 (pz2bpy: 2,6-di(pyrazin-2-yl)-4,4'-bipyridine) showed a better peak activity, however, followed by a progressive decay. After 24 hours, complexes C1, C2 and C3 had reached TONs of 18, 35 and 52 under blue light and 14, 20 and 47 under green light, respectively, and were still found to be active. Their photophysical and electronic properties are discussed to rationalize the photocatalytic trends.

Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses.

The optimization of a novel series of non-nucleoside reverse transcriptase inhibitors (NNRTI) led to the identification of pyridone 36. In cell cultures, this new NNRTI shows a superior potency profile against a range of wild type and clinically relevant, resistant mutant HIV viruses. The overall favorable preclinical pharmacokinetic profile of 36 led to the prediction of a once daily low dose regimen in human. NNRTI 36, now known as MK-1439, is currently in clinical development for the treatment of HIV infection.

Nicotinic acids: liver-targeted SCD inhibitors with preclinical anti-diabetic efficacy.

An in vitro screening protocol was used to transform a systemically-distributed SCD inhibitor into a liver-targeted compound. Incorporation of a key nicotinic acid moiety enables molecular recognition by OATP transporters, as demonstrated by uptake studies in transfected cell lines, and likely serves as a critical component of the observed liver-targeted tissue distribution profile. Preclinical anti-diabetic oGTT efficacy is demonstrated with nicotinic acid-based, liver-targeting SCD inhibitor 10, and studies with a close-structural analog devoid of SCD1 activity, suggest this efficacy is a result of on-target activity.

The identification of 4,7-disubstituted naphthoic acid derivatives as UDP-competitive antagonists of P2Y14.

A weak, UDP-competitive antagonist of the pyrimidinergic receptor P2RY(14) with a naphthoic acid core was identified through high-throughput screening. Optimization provided compounds with improved potency but poor pharmacokinetics. Acylglucuronidation was determined to be the major route of metabolism. Increasing the electron-withdrawing nature of the substituents markedly reduced glucuronidation and improved the pharmacokinetic profile. Additional optimization led to the identification of compound 38 which is an 8 nM UDP-competitive antagonist of P2Y(14) with a good pharmacokinetic profile.

Difluoroethylamines as an amide isostere in inhibitors of cathepsin K.

The trifluoroethylamine group found in cathepsin K inhibitors like odanacatib can be replaced by a difluoroethylamine group. This change increased the basicity of the nitrogen which positively impacted the log D. This translated into an improved oral bioavailability in pre-clinical species. Difluoroethylamine compounds exhibit a similar potency against cathepsin K and selectivity profile against other cathepsins when compared to trifluoroethylamine analogs.

The discovery and synthesis of highly potent subtype selective phosphodiesterase 4D inhibitors.

The SAR study of a series of 6-aryloxymethyl-8-aryl substituted quinolines is described. Optimization of the series led to the discovery of compound 26b, a highly potent (IC50=0.6 nM) and selective PDE4D inhibitor with a 75-fold selectivity over the A, B, and C subtypes and over 18,000-fold selectivity against other PDE family members. Rat pharmacokinetics and tissue distribution are also summarized.

Synthesis and biological activity of a potent and orally bioavailable SCD inhibitor (MF-438).

A series of stearoyl-CoA desaturase 1 (SCD1) inhibitors were developed. Investigations of enzyme potency and metabolism led to the identification of the thiadiazole-pyridazine derivative MF-438 as a potent SCD1 inhibitor. MF-438 exhibits good pharmacokinetics and metabolic stability, thereby serving as a valuable tool for further understanding the role of SCD inhibition in biological and pharmacological models of diseases related to metabolic disorders.

Alkyl-bridged substituted 8-arylquinolines as highly potent PDE IV inhibitors.

Substituted 8-arylquinoline analogs bearing alkyl-linked side chain were identified as potent inhibitors of type 4 phophodiesterase. These compounds address the potential liabilities of the clinical candidate L-454560. The pharmacokinetic profile of the best analogs and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.

Structure-activity relationships and pharmacokinetic parameters of quinoline acylsulfonamides as potent and selective antagonists of the EP(4) receptor.

A new series of EP(4) antagonists based on a quinoline acylsulfonamide scaffold have been identified as part of our on-going efforts to develop treatments for chronic inflammation. These compounds show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. Acceptable pharmacokinetic profiles have also been demonstrated across a series of preclinical species.

Design, synthesis, and biological evaluation of 8-biarylquinolines: a novel class of PDE4 inhibitors.

The structure-activity relationship of a novel series of 8-biarylquinolines acting as type 4 phosphodiesterase (PDE4) inhibitors is described herein. Prototypical compounds from this series are potent and non-selective inhibitors of the four distinct PDE4 (IC(50)<10 nM) isozymes (A-D). In a human whole blood in vitro assay, they inhibit (IC(50)<0.5 microM) the LPS-induced release of the cytokine TNF-alpha. Optimized inhibitors were evaluated in vivo for efficacy in an ovalbumin-induced bronchoconstriction model in conscious guinea pigs. Their propensity to produce an emetic response was evaluated by performing pharmacokinetic studies in squirrel monkeys. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of efficacy over emesis.

Nitrogen-bridged substituted 8-arylquinolines as potent PDE IV inhibitors.

Potent inhibitors of the human PDE IV enzyme are described. Substituted 8-arylquinoline analogs bearing nitrogen-linked side chain were identified as potent inhibitors based on the SAR described herein. The pharmacokinetic profile of the best analog and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.

Identification of a potent and selective non-basic cathepsin K inhibitor.

Based on our previous study with trifluoroethylamine as a P2-P3 amide isostere of cathepsin K inhibitor, further optimization led to identification of compound 22 (L-873724) as a potent and selective non-basic cathepsin K inhibitor. This compound showed excellent pharmacokinetics and efficacy in an ovariectomized (OVX) rhesus monkey model. The volumes of distribution close to unity were consistent with this compound not being lysosomotropic, which is a characteristic of basic cathepsin K inhibitors.

Discovery of a substituted 8-arylquinoline series of PDE4 inhibitors: structure-activity relationship, optimization, and identification of a highly potent, well tolerated, PDE4 inhibitor.

The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4 (IC(50)<1nM) and also of LPS-induced TNF-alpha release in human whole blood (IC(50)<0.5microM). The same compounds are potent inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC(50)<0.1mg/kg ip) but require a dose of about 10mg/kg po in the squirrel monkey to produce an emetic response. From this series of compounds, 23a (L-454,560) was identified as an optimized compound.