Browsing by Author "Laha, Joydev K."

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Carboetomidate: A Pyrrole Analog of Etomidate Designed Not to Suppress Adrenocortical Function
(Anesthesiology, 2011-03) Cotten, Joseph F.; Forman, Stuart A.; Laha, Joydev K.; Cuny, Gregory D.; Husain, Shaukat; Miller, Keith W.; Nguyen, Hieu H.; Kelly, Elizabeth W.; Stewart, Deirdre; Liu, Aiping; Raines, Douglas E.
Background: Etomidate is a sedative-hypnotic that is often used in critically ill patients because it provides superior hemodynamic stability. However it also binds with high affinity to 11?-hydroxylase, potently suppressing synthesis of steroids by the adrenal gland that are necessary for survival. We report the results of studies to define the pharmacology of (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate), a pyrrole analogue of etomidate specifically designed not to bind with high affinity to 11?-hydroxylase. Methods: The hypnotic potency of carboetomidate was defined in tadpoles and rats using loss of righting reflex assays. Its ability to enhance wild-type ?1?2?2L and etomidate-insensitive mutant ?1?2(M286W)?2L human ?-aminobutyric acid type A receptor activities was assessed using electrophysiological techniques. Its potency for inhibiting in vitro cortisol synthesis was defined using a human adrenocortical cell assay. Its effects on in vivo hemodynamic and adrenocortical function were defined in rats. Results: Carboetomidate was a potent hypnotic in tadpoles and rats. It increased currents mediated by wild-type, but not etomidate-insensitive mutant ?-aminobutyric acid type A receptors. Carboetomidate was three orders of magnitude less potent an inhibitor of in vitro cortisol synthesis by adrenocortical cells than was etomidate. In rats, carboetomidate caused minimal hemodynamic changes and did not suppress adrenocortical function at hypnotic doses. Conclusions: Carboetomidate is an etomidate analogue that retains many of etomidate’s beneficial properties, but is dramatically less potent as an inhibitor of adrenocortical steroid synthesis. Carboetomidate is a promising new sedative-hypnotic for potential use in critically ill patients in whom adrenocortical suppression is undesirable.
Diaminothiazoles Modify Tau Phosphorylation and Improve the Tauopathy in Mouse Models
(Journal of BIological Chemistry, 2013-07) Zhang, Xuemei; Hernandez, Israel; Rei, Damien; Mair, Waltraud; Laha, Joydev K.; Cornwell, Madison E.; Cuny, Gregory D.; Tsai, Li-Huei; Steen, Judith A. J.; Kosik, Kenneth S.
Although Tau accumulation is a feature of several neurodegenerative conditions, treatment options for these conditions are nonexistent. Targeting Tau kinases represents a potential therapeutic approach. Small molecules in the diaminothiazole class are potent Tau kinase inhibitors that target CDK5 and GSK3?. Lead compounds from the series have IC50 values toward CDK5/p25 and GSK3? in the low nanomolar range and no observed toxicity in the therapeutic dose range. Neuronal protective effects and decreased PHF-1 immunoreactivity were observed in two animal models, 3×Tg-AD and CK-p25. Treatment nearly eliminated Sarkosyl-insoluble Tau with the most prominent effect on the phosphorylation at Ser-404. Treatment also induced the recovery of memory in a fear conditioning assay. Given the contribution of both CDK5/p25 and GSK3? to Tau phosphorylation, effective treatment of tauopathies may require dual kinase targeting.
In Vivo and In Vitro Pharmacological Studies of Methoxycarbonyl-Carboetomidate
(Anethesia and Analgesia, 2013-08) Pejo, Ervin; Cotten, Joseph F.; Kelly, Elizabeth W.; Ge, Ri Le; Cuny, Gregory D.; Laha, Joydev K.; Liu, Jifeng; Lin, Xiang Jie; Raines, Douglas E.
Background—We previously developed two etomidate analogs that retain etomidate’s favorable hemodynamic properties, but whose adrenocortical effects are reduced in duration or magnitude. Methoxycarbonyl-etomidate (MOC-etomidate) is rapidly metabolized and ultra-short acting whereas (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate) does not potently inhibit 11?-hydroxylase. We hypothesized that MOC-etomidate’s labile ester could be incorporated into carboetomidate to produce a new agent that possesses favorable properties individually found in each agent. We describe the synthesis and pharmacology of methoxycarbonyl-(R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (MOC-carboetomidate), a “soft” analog of carboetomidate. Methods—MOC-carboetomidate’s octanol:water partition coefficient was determined chromatographically and compared with those of etomidate, carboetomidate, and MOC-etomidate. MOC-carboetomidate’s EC50 and ED50 for loss of righting reflexes (LORR) were measured in tadpoles and rats, respectively. Its effect on gamma-aminobutyric acid A (GABAA) receptor function was assessed using two-microelectrode voltage clamp electrophysiological techniques and its metabolic stability was determined in pooled rat blood using high performance liquid chromatography. Its duration of action and effects on arterial blood pressure and adrenocortical function were assessed in rats. Results—MOC-carboetomidate’s octanol:water partition coefficient was 3300 ± 280, whereas those for etomidate, carboetomidate, and MOC-etomidate were 800 ± 180, 15000 ± 3700, and 190 ± 25, respectively. MOC-carboetomidate’s EC50 for LORR in tadpoles was 9 ± 1 µM and its EC50 for LORR in rats was 13 ± 5 mg/kg. At 13 µM, MOC-carboetomidate enhanced GABAA receptor currents by 400 ± 100%. Its metabolic half-life in pooled rat blood was 1.3 minutes. The slope of a plot of the duration of LORR in rats versus the logarithm of the hypnotic dose was significantly shallower for MOC-carboetomidate than for carboetomidate (4 ± 1 vs. 15 ± 3, respectively; p = 0. 0004123). At hypnotic doses, the effects of MOC-carboetomidate on arterial blood pressure and adrenocortical function were not significantly different from those of vehicle alone. Conclusions—MOC-carboetomidate is a GABAA receptor modulator with potent hypnotic activity that is more rapidly metabolized and cleared from the brain than carboetomidate, maintains hemodynamic stability similar to carboetomidate, and does not suppress adrenocortical function.
Structure–activity relationship study of 2,4-diaminothiazoles as Cdk5/p25 kinase inhibitors
(Bioorganic and Medicinal Chemistry Letters, 2012-04) Laha, Joydev K.; Zhang, Xuemei; Qiao, Lixin; Chatterjee, Snigdha; Robinson, Shaughnessy; Kosik, Kenneth S.; Cuny, Gregory D.
Cdk5/p25 has emerged as a principle therapeutic target for numerous acute and chronic neurodegenerative diseases, including Alzheimer’s disease. A structure–activity relationship study of 2,4-diaminothiazole inhibitors revealed that increased Cdk5/p25 inhibitory activity could be accomplished by incorporating pyridines on the 2-amino group and addition of substituents to the 2- or 3-position of the phenyl ketone moiety. Interpretation of the SAR results for many of the analogs was aided through in silico docking with Cdk5/p25 and calculating protein hydrations sites using WaterMap. Finally, improved in vitro mouse microsomal stability was also achieved.
Structure–activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors
(Bioorganic and Medicinal Chemistry Letters, 2009-08) Cuny, Gregory D.; Yu, Paul B.; Laha, Joydev K.; Xing, Xuechao; Liu, Ji-Feng; Lai, Carol S.; Deng, Donna Y.; Sachidanandan, Chetana; Bloch, Kenneth D.; Peterson, Randall T.
A structure–activity relationship study of dorsomorphin, a previously identified inhibitor of SMAD 1/5/8 phosphorylation by bone morphogenetic protein (BMP) type 1 receptors ALK2, 3, and 6, revealed that increased inhibitory activity could be accomplished by replacing the pendent 4-pyridine ring with 4-quinoline. The activity contributions of various nitrogen atoms in the core pyrazolo[1,5-a]pyrimidine ring were also examined by preparing and evaluating pyrrolo[1,2-a]pyrimidine and pyrazolo[1,5-a]pyridine derivatives. In addition, increased mouse liver microsome stability was achieved by replacing the ether substituent on the pendent phenyl ring with piperazine. Finally, an optimized compound 13 (LDN-193189 or DM-3189) demonstrated moderate pharmacokinetic characteristics (e.g., plasma t1/2 = 1.6 h) following intraperitoneal administration in mice. These studies provide useful molecular probes for examining the in vivo pharmacology of BMP signaling inhibition.