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1.
J Med Chem ; 65(5): 3786-3797, 2022 03 10.
Article in English | MEDLINE | ID: mdl-35175768

ABSTRACT

Results from recently completed clinical studies suggest the dopamine D1 receptor positive allosteric modulator (PAM) mevidalen (1) could offer unique value for lewy body dementia (LBD) patients. In nonclinical assessments, 1 was mainly eliminated by CYP3A4-mediated metabolism, therefore at the risk of being a victim of drug-drug interactions (DDI) with CYP3A4 inhibitors and inducers. An effort was initiated to identify a new D1 PAM with an improved DDI risk profile. While attempts to introduce additional metabolic pathways mediated by other CYP isoforms failed to provide molecules with an acceptable profile, we discovered that the relative contribution of CYP-mediated oxidation and UGT-mediated conjugation could be tuned to reduce the CYP3A4-mediated victim DDI risk. We have identified LY3154885 (5), a D1 PAM that possesses similar in vitro and in vivo pharmacologic properties as 1, but is metabolized mainly by UGT, predicting it could potentially offer lower victim DDI risk in clinic.


Subject(s)
Cytochrome P-450 CYP3A , Neuroprotective Agents , Receptors, Dopamine D1/antagonists & inhibitors , Allosteric Regulation , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A Inhibitors , Drug Interactions , Humans , Receptors, Dopamine D1/metabolism
2.
J Med Chem ; 62(19): 8711-8732, 2019 10 10.
Article in English | MEDLINE | ID: mdl-31532644

ABSTRACT

Clinical development of catechol-based orthosteric agonists of the dopamine D1 receptor has thus far been unsuccessful due to multiple challenges. To address these issues, we identified LY3154207 (3) as a novel, potent, and subtype selective human D1 positive allosteric modulator (PAM) with minimal allosteric agonist activity. Conformational studies showed LY3154207 adopts an unusual boat conformation, and a binding pose with the human D1 receptor was proposed based on this observation. In contrast to orthosteric agonists, LY3154207 showed a distinct pharmacological profile without a bell-shaped dose-response relationship or tachyphylaxis in preclinical models. Identification of a crystalline form of free LY3154207 from the discovery lots was not successful. Instead, a novel cocrystal form with superior solubility was discovered and determined to be suitable for development. This cocrystal form was advanced to clinical development as a potential first-in-class D1 PAM and is now in phase 2 studies for Lewy body dementia.


Subject(s)
Isoquinolines/pharmacology , Receptors, Dopamine D1/agonists , Acetylcholine/metabolism , Administration, Oral , Allosteric Regulation/drug effects , Animals , Binding Sites , Crystallography, X-Ray , Cyclic AMP/metabolism , HEK293 Cells , Half-Life , Humans , Isoquinolines/chemistry , Isoquinolines/pharmacokinetics , Kidney/drug effects , Kidney/metabolism , Locomotion/drug effects , Mice , Molecular Conformation , Protein Isoforms/agonists , Protein Isoforms/metabolism , Rats , Receptors, Dopamine D1/metabolism , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Small Molecule Libraries/pharmacology , Structure-Activity Relationship
3.
J Pharm Sci ; 105(10): 3105-3114, 2016 10.
Article in English | MEDLINE | ID: mdl-27492963

ABSTRACT

Control and optimization of the physical properties of a drug substance (DS) are critical to the development of robust drug product manufacturing processes and performance. A lack of isolatable, for example, crystalline, DS solid forms can present challenges to achieving this control. In this study, an isolation scheme for an amorphous DS was developed and integrated into the synthetic route producing DS with optimized properties. An inert absorbent excipient (Neusilin® US2) was used to isolate the DS via a novel antisolvent scheme as the final step of the route. Isolation was executed at kilogram scale utilizing conventional equipment. The resulting 50 wt% DS:Neusilin complex had improved physical stability and exceptional micromeritic and tableting properties. Improved dissolution was observed and attributed to enhanced dispersion and increased surface area. Characterization data suggest a high degree of penetration of the DS into the Neusilin, with DS occupying 70% of mesopore and 12% of macropore volume. This approach has application in the isolation and particle engineering of difficult to isolate DS without additional unit operation, such as spray drying, and has the potential for a high degree of optimization and control of physical properties over the course of DS development.


Subject(s)
Aluminum Compounds/chemistry , Aluminum Compounds/isolation & purification , Magnesium Compounds/chemistry , Magnesium Compounds/isolation & purification , Silicates/chemistry , Silicates/isolation & purification , Aluminum Silicates/chemistry , Aluminum Silicates/isolation & purification , Compressive Strength , Magnesium/chemistry , Magnesium/isolation & purification , Particle Size , Surface Properties , X-Ray Diffraction/methods
4.
J Med Chem ; 52(22): 6958-61, 2009 Nov 26.
Article in English | MEDLINE | ID: mdl-19860433

ABSTRACT

The design, synthesis, and biological characterization of an orally active prodrug (3) of gemcitabine are described. Additionally, the identification of a novel co-crystal solid form of the compound is presented. Valproate amide 3 is orally bioavailable and releases gemcitabine into the systemic circulation after passing through the intestinal mucosa. The compound has entered clinical trials and is being evaluated as a potential new anticancer agent.


Subject(s)
Antineoplastic Agents/chemistry , Deoxycytidine/analogs & derivatives , Prodrugs/chemistry , Prodrugs/pharmacology , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Transformation, Neoplastic , Colonic Neoplasms/drug therapy , Crystallization , Crystallography, X-Ray , Cytidine/chemistry , Deoxycytidine/administration & dosage , Deoxycytidine/chemistry , Deoxycytidine/pharmacology , Humans , Mice , Models, Molecular , Molecular Conformation , Prodrugs/administration & dosage , Prodrugs/chemical synthesis , Solubility , Gemcitabine
5.
Mol Pharm ; 5(6): 946-55, 2008.
Article in English | MEDLINE | ID: mdl-19434850

ABSTRACT

Amorphous solids and crystalline salts are both of interest as a means of improving the dissolution characteristics and apparent solubility of poorly water soluble active pharmaceutical ingredients which have low bioavailability in humans. The theory and selection of both crystalline drug substance salt forms and amorphous products have been extensively studied. However, less is known about the impact of different counterions on the properties of amorphous drug substance salts. In this study, several salts of either nicardipine or propranolol were prepared and characterized with respect to glass transition temperature, crystallization tendency and moisture sorption behavior. Although the moisture sorption behavior and crystallization tendency varied depending on the counterion used, no trends were readily apparent. The glass transition temperature was found to be dependent on the counterion used to form the salt, and was higher in all instances for the salts than for the neutral compound. Several molecular descriptors were calculated for the various counterions, and multivariate analysis was used to build a model that successfully correlated Tg with a number of these parameters. Important parameters which influenced Tg included counterion pKa and electrophilicity index. In conclusion, it is apparent that, as for crystalline salts, the counterion has an effect on the properties of amorphous materials.


Subject(s)
Nicardipine/chemistry , Organic Chemicals/chemistry , Pharmaceutical Preparations/chemistry , Propranolol/chemistry , Salts/chemistry , Adsorption , Chemistry, Pharmaceutical , Crystallization , Glass/chemistry , Humans , Humidity , Molecular Structure , Multivariate Analysis , Solubility , Technology, Pharmaceutical/methods , Temperature , Transition Temperature , Water/chemistry
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