Synthesis and Preclinical Characterization of LY3154885, a Human Dopamine D1 Receptor Positive Allosteric Modulator with an Improved Nonclinical Drug-Drug Interaction Risk Profile.

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.

Prevalence of rheumatoid arthritis in the French West Indies: Results of the EPPPRA study in Martinique.

OBJECTIVES: Studies suggest that rheumatoid arthritis (RA) is less frequent in African populations. However, no recent precise data exists for Afro-Caribbeans. The EPPPRA project is a prospective epidemiological survey to describe prevalence and clinical aspects of RA in the French West Indies (Martinique, Guadeloupe, French Guiana). METHODS: EPPPRA involved all rheumatologists from the French West Indies who included all patients with a known clinical diagnosis of RA, during a one-year period. We outline here results for Martinique. RESULTS: EPPPRA estimated an overall world age-standardized prevalence of RA at 0.10% [95% CI 0.09% to 0.11%] in Martinique, with a high female predominance (88.1%) and 93.1% of self-reported Afro-Caribbeans. Mean age at diagnosis was 49.6±16.0 years. A majority of subjects presented at least 4 criteria points from the 1987 American College of Rheumatology (ACR) classification (94.4%) and at least 6 points (78.2%) from the 2010 ACR/European League Against Rheumatism (EULAR) classification. A high immune seropositivity rate was highlighted (84.2%). Despite functional impact observed in 40.5% of patients, 71.4% presented a low disease activity level. Methotrexate was the most common ongoing treatment (73%), followed by biotherapies (24.4%). Numerous patients (68.6%) received a steroid regimen. Cardiovascular risk factors were very frequent, contrasting with a very low tobacco use (8.7%), CONCLUSION: This work outlines low standardized prevalence of RA in a French Afro-Caribbean population with specific characteristics (high female predominance, high immune seropositivity, low tobacco use). Despite easy access to care and biotherapies, approximately half of RA patients still present destructive disease with functional impact.

Dengue fever in patients under biologics.

Dengue fever (DF) is an epidemic viral mosquito-borne infection limited to tropical and subtropical countries. Biological therapies have been frequently used for the last 15 years in the treatment of inflammatory rheumatic conditions like rheumatoid arthritis. However, no data is available regarding the characteristics of this infection in patients on biological therapy. Yet, numerous patients on biotherapy have holidays in countries where DF exists. Moreover, the mosquitoes Aedes albopictus, vector of this viral disease, is now found in some developed countries such as southern Europe and the USA, allowing the possibility of a DF outbreak. We conducted a survey of individuals on biotherapy and described a case series of the patients experiencing DF. Our 8 patients on biotherapy (anti-TNF, n=6; rituximab, n=2) for a rheumatic condition did not experience severe DF.

Discovery of (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide, a potent and orally efficacious mGlu5 receptor negative allosteric modulator.

A novel series of selective negative allosteric modulators (NAMs) for metabotropic glutamate receptor 5 (mGlu5) was discovered from an isothiazole scaffold. One compound of this series, (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide (24), demonstrated satisfactory pharmacokinetic properties and, following oral dosing in rats, produced dose-dependent and long-lasting mGlu5 receptor occupancy. Consistent with the hypothesis that blockade of mGlu5 receptors will produce analgesic effects in mammals, compound 24 produced a dose-dependent reduction in paw licking responses in the formalin model of persistent pain.