A series of benzotriazole phenyldifluoromethylphosphonic acids were found to be potent PTP-1B inhibitors. Molecular modeling on the X-ray crystal structure of the lead structure led to the design of ...potent PTP-1B inhibitors that show moderate selectivity against TC-PTP, a very closely related protein tyrosine phosphatase.
By inserting an oxygen link between the 3-fluorophenyl and the lactone ring of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methanesulfonylphenyl)-2(5H)-furanone
1 (DFU), analogs with enhanced
in vitro COX-2 ...inhibitory potency as well as
in vivo potency in models of inflammation were obtained.
By inserting an oxygen link between the aryl group and the lactone ring, analogs with enhanced COX-2 and antiinflammatory activity could be obtained.
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.
Renin is the first enzyme in the renin-angiotensin-aldosterone system which is the principal regulator of blood pressure and hydroelectrolyte balance. Previous studies suggest that cathepsin B is the ...activator of the prorenin zymogen. Here, we show no difference in plasma renin activity, or mean arterial blood pressure between wild-type and cathepsin B knockout mice. To account for potential gene compensation, a potent, selective, reversible cathepsin B inhibitor was developed to determine the role of cathepsin B on prorenin processing in rats. Pharmacological inhibition of cathepsin B in spontaneously hypertensive and double transgenic rats did not result in a reduction in renal mature renin protein levels or plasma renin activity. We conclude that cathepsin B does not play a significant role in this process in rodents.
MK-0674 is a potent and selective cathepsin K inhibitor from the same structural class as odanacatib with a comparable inhibitory potency profile against Cat K. It is orally bioavailable and exhibits ...long half-life in pre-clinical species. In vivo studies using deuterated MK-0674 show stereoselective epimerization of the alcohol stereocenter via an oxidation/reduction cycle. From in vitro incubations, two metabolites could be identified: the hydroxyleucine and the glucuronide conjugate which were confirmed using authentic synthetic standards.
Our series of competitive antagonists against the G-protein coupled receptor P2Y sub(14 were found to be highly shifted in the presence of serum (99% protein bound). A binding assay using 2% human ...serum albumin (HSA) was developed to guide further SAR studies and led to the identification of the zwitterion 2, which is substantially less shifted (18-fold) than our previous lead compound 1 (323-fold). However, as the bioavailability of 2 was low, a library of ester pro-drugs was prepared ( 7a- 7j) and assessed in vitro. The most interesting candidates were then profiled in vivo and led to the identification of the pro-drug 7j, which possesses a substantially improved pharmacokinetic profile.)
A weak, UDP-competitive antagonist of the pyrimidinergic receptor P2RY sub(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) sub(1)4 with a good pharmacokinetic profile.
Pyridazinone was found to be an excellent core template for selective COX-2 inhibitors. Two potent, selective and orally active COX-2 inhibitors, which were highly efficacious in rat paw edema and ...rat pyresis models, have been obtained.
Pyridazinone was found to be an excellent core template for selective COX-2 inhibitors.
Our series of competitive antagonists against the G-protein coupled receptor P2Y
14 were found to be highly shifted in the presence of serum (>99% protein bound). A binding assay using 2% human serum ...albumin (HSA) was developed to guide further SAR studies and led to the identification of the zwitterion
2, which is substantially less shifted (18-fold) than our previous lead compound
1 (323-fold). However, as the bioavailability of
2 was low, a library of ester pro-drugs was prepared (
7a–
7j) and assessed in vitro. The most interesting candidates were then profiled in vivo and led to the identification of the pro-drug
7j, which possesses a substantially improved pharmacokinetic profile.
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.
