Author: Yadav, Anil K ; Gupta, Anumegha ; Tiwari, Meenakshi ; Sharma, Alka ; Shrivastav, Tulsidas G ; Yadav, Pramod K ; Pandey, Ashutosh N ; Pandey, Ajai K ; Chaube, Shail K

Cyclic nucleotide phosphodiesterases (PDEs) are group of enzymes responsible for the hydrolysis of cyclic adenosine 3', 5' monophosphate (cAMP) and cyclic guanosine 3', 5' monophosphate (cGMP) levels in wide variety of cell types. These PDEs are detected in encircling granulosa cells or in oocyte with in follicular microenvironment and responsible for the decrease of cAMP and cGMP levels in mammalian oocytes. A transient decrease of cAMP level initiates downstream pathways to cause spontaneous meiotic resumption from diplotene arrest and induces oocyte maturation. The nonspecific PDE inhibitors (caffeine, pentoxifylline, theophylline, IBMX etc.) as well as specific PDE inhibitors (cilostamide, milrinone, org 9935, cilostazol etc.) have been used to elevate cAMP level and inhibit meiotic resumption from diplotene arrest and oocyte maturation, ovulation, fertilization and pregnancy rates both in vivo as well as under in vitro culture conditions. The PDEs inhibitors are used as powerful experimental tools to demonstrate cyclic nucleotide mediated changes in ovarian functions and thereby fertility. Indeed, non-hormonal nature and reversible effects of nonspecific as well as specific PDE inhibitors hold promise for the development of novel therapeutic drugs for female fertility regulation.

01 May 2018·TetrahedronQ3 · CHEMISTRY

Syntheses of PDE3A inhibitor ORG9935 and determination of the absolute stereochemistries of its enantiomers by X-ray crystallography

Q3 · CHEMISTRY

Article

Author: Jakkaraj, Sudhakar ; Young, Victor G ; Georg, Gunda I

Two synthetic methods were developed for the synthesis of PDE3A inhibitor ORG9935. The first one proceeds in six steps and 34% overall yield and the second one in five steps and an overall yield of 69% starting from commercially available starting material 5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid (6). The enantiomers of ORG9935 were separated by chiral column chromatography and the absolute stereochemistry of the (+)-enantiomer, ORG20865 was determined by X-ray crystallography to possess the (S)-configuration. The (-)-enantiomer, ORG20864, was therefore assigned the (R)-stereochemistry. The biologically less active (+)-isomer ORG20865 was converted to racemic ORG9935 under basic conditions, which then can be separated again into the enantiomers. The crystal structure of ORG20865 is notable for having the highest Z' for any known pharmaceutical substance.

01 Feb 2014·Life SciencesQ3 · MEDICINE

Cilostazol administered to female mice induces ovulation of immature oocytes: A contraceptive animal model

Q3 · MEDICINE

Article

Author: Sayes, Christie M ; Taiyeb, Ahmed M ; Dees, William L ; Kraemer, Duane C ; Ridha, Mundhir T

AIMSBoth Cilostamide and Org 9935 are phosphodiesterase 3A (PDE3A) inhibitors that were evaluated in rodents and monkeys for their non-steroidal contraceptive properties. Although both compounds inhibited oocyte maturation, an adverse effect on heart rate was observed. Cilostazol (CLZ, Pletal) is a safe PDE3A inhibitor that was recently reported to block pregnancy in naturally cycling mice. In this study, the dose, frequency, time of administration, and reversibility effects of CLZ on oocyte maturation were defined using superovulated mice.MAIN METHODSSuperovulated mice were gavaged once or twice with 0, 7.5, or 15 mg CLZ at various times around the ovulatory stimulus. Ovulated oocytes were then evaluated for maturational stages.KEY FINDINGSCLZ resulted in mice ovulating significant numbers of immature oocytes when administered anytime between 9h before the ovulatory stimulus and 2 h after the stimulus. This inhibitory effect was greater when CLZ dose was increased, administered twice or closer to the time of the ovulatory stimulus. Conversely, ovulated immature oocytes resumed maturation in oviducts when CLZ dose was reduced, administered once and away from the time of the stimulus.SIGNIFICANCEControlling CLZ dose, frequency, and time of administration produced mice ovulating immature oocytes at different stages, which may be an advantage over the conventional collection of immature oocytes from ovaries. More importantly, the capability of a clinically approved PDE3A inhibitor, with a reasonable margin of safety, to arrest oocyte maturation over a wide range of administration times and at doses extrapolated from human therapeutic doses demonstrates the contraceptive capacity of CLZ.

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Asthma	Discovery	NL	Organon & Co.	-

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