We previously described a negative allosteric modulator (NAM) of FSHR (ADX61623) that blocked FSH-induced cAMP and progesterone production but did not block estradiol production. That FSHR NAM did not affect FSH-induced preovulatory follicle development as evidenced by the lack of an effect on the number of FSH-dependent oocytes found in the ampullae following ovulation with hCG. A goal is the development of a nonsteroidal contraceptive. Toward this end, a high-throughput screen using human FSHR identified an additional nonsteroidal small molecule (ADX68692). Although ADX68692 behaved like ADX61623 in inhibiting production of cAMP and progesterone, it also inhibited FSH-induced estradiol in an in vitro rat granulosa primary cell culture bioassay. When immature, noncycling female rats were injected subcutaneously or by oral dosing prior to exogenous FSH administration, it was found that ADX68692 decreased the number of oocytes recovered from the ampullae. The estrous cycles of mature female rats were disrupted by administration by oral gavage of 25 mg/kg and 10 mg/kg ADX68692. In the highest dose tested (25 mg/kg), 55% of animals cohabited with mature males had implantation sites compared to 33% in the 10 mg/kg group and 77% in the control group. A surprising finding was that a structural analog ADX68693, while effectively blocking progesterone production with similar efficacy as ADX68692, did not block estrogen production and despite better oral availability did not decrease the number of oocytes found in the ampullae even when used at 100 mg/kg. These data demonstrate that because of biased antagonism of the FSHR, nonsteroidal contraception requires that both arms of the FSHR steroidogenic pathway must be effectively blocked, particularly estrogen biosynthesis. Thus, a corollary to these findings is that it seems reasonable to propose that the estrogen-dependent diseases such as endometriosis may benefit from inhibition of FSH action at the ovary using the FSHR NAM approach.

A series of potent non-acetylinic negative allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5 NAMs) was developed starting from HTS screening hit 1. Potency was improved via iterative SAR, and physicochemical properties were optimized to deliver orally bioavailable compounds acceptable for in vivo testing. A lead molecule from the series demonstrated dose-dependent activity in the second phase of the rat formalin test from 30 mg/kg, and a preliminary PK/PD relationship was established.

ADX71943 is a potent and selective GABAb receptor positive allosteric modulator (PAM) which exhibits poor aqueous solubility at all physiologically relevant pHs. The aim of this study was to identify an adequate formulation to improve the solubility of ADX71943 to achieve a sufficiently high plasma exposure after oral administration to support the toxicology program. Considering the overall physicochemical properties and the low solubility of ADX71943 in a variety of solvents, solid dispersion, and particle size reduction have been successfully chosen as potential strategies to improve its oral bioavailability. Both technologies have proven useful in improving the in vitro dissolution profile and as a result of the solubility enhancement, higher bioavailability was obtained in vivo. As the solid dispersion gave better bioavailability (30-fold compared with the neat active pharmaceutical ingredient (API)), this formulation was selected for the toxicology study. Changing the crystalline form of ADX71943 into amorphous state by preparing a solid dispersion has greatly improved its oral bioavailability and has allowed achieving the required plasma concentration needed in toxicology studies.

You have accessJournal of UrologyBladder and Urethra: Anatomy, Physiology and Pharmacology I1 Apr 2012268 A NOVEL APPROACH TO TREAT OVERACTIVE BLADDER BY POSITIVE MODULATION OF THE GABA-B RECEPTOR (GABA-BR) WITH ADX71441 Sonia Poli, Mikhail Kalinichev, Lam Tang, Charlotte Keywood, Manfred Schneider, Béatrice Bonnet, and Géraldine Parenty Sonia PoliSonia Poli Plan les Ouates, Switzerland More articles by this author , Mikhail KalinichevMikhail Kalinichev Plan les Ouates, Switzerland More articles by this author , Lam TangLam Tang Plan les Ouates, Switzerland More articles by this author , Charlotte KeywoodCharlotte Keywood Plan les Ouates, Switzerland More articles by this author , Manfred SchneiderManfred Schneider Plan les Ouates, Switzerland More articles by this author , Béatrice BonnetBéatrice Bonnet Plan les Ouates, Switzerland More articles by this author , and Géraldine ParentyGéraldine Parenty Plan les Ouates, Switzerland More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.325AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES GABA is important for micturition control. The GABA-BR agonist baclofen reduces urethral resistance and detrusor overactivity in patients with spasticity. However, baclofen's side effects limit its use in overactive bladder (OAB). Anti-muscarinics are standard treatment for OAB, but these have use-limiting anticholinergic effects. ADX71441 is a novel, orally active GABA-BR positive allosteric modulator with potentially improved safety and pharmacokinetics over baclofen and no anticholinergic side effect profile. ADX71441 was studied in a diuretic stress-induced preclinical model of OAB and its efficacy compared to the muscarinic oxybutynin. METHODS Male C57BL/6 mice, food-restricted pre-experiment, were left untreated or given vehicle, ADX71441 1, 3, 10 mg/kg or oxybutynin 100 mg/kg p.o. (n=8/group). Treated mice received water 1ml s.c. 55 min later, followed by furosemide. First micturition event latency, micturition frequency, total and average micturition volumes were assessed for 90 min post diuretic. RESULTS Administration of ADX71441 dose-dependently prolonged micturition latency, reduced micturition frequency, and volumes. Efficacy was statistically significant for ADX71441 (10 mg/kg) which returned most parameters to untreated control levels and was similar to oxybutynin. CONCLUSIONS In the diuretic stress-induced OAB model, ADX71441 showed clinically relevant improvements on urinary parameters, comparable to oxybutinin at the 10 mg/kg dose. GABA-BR positive modulation by ADX71441 has potential as a novel approach to OAB treatment. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e109 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.Metrics Author Information Sonia Poli Plan les Ouates, Switzerland More articles by this author Mikhail Kalinichev Plan les Ouates, Switzerland More articles by this author Lam Tang Plan les Ouates, Switzerland More articles by this author Charlotte Keywood Plan les Ouates, Switzerland More articles by this author Manfred Schneider Plan les Ouates, Switzerland More articles by this author Béatrice Bonnet Plan les Ouates, Switzerland More articles by this author Géraldine Parenty Plan les Ouates, Switzerland More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Allosteric modulators of metabotropic glutamate receptors (mGluR) subtypes 1-8 have been shown to offer a valid way to develop small molecule non aminoacid-like therapeutics that can be administered orally and that readily cross the blood-brain barrier. Allosteric modulators of glutamatergic receptors and in particular mGluR5 have emerged as a novel and highly desirable class of compounds for the treatment of central nervous system (CNS) disorders and peripheral disorders. This article provides medicinal chemistry highlights around the chemical classes of potent and highly selective mGluR5 negative allosteric modulators (NAMs) and their therapeutic potential. In addition, it describes the medicinal chemistry approach from the discovery to the clinical candidate selection of a new series of heteroaryl-butynylpyridines targeting mGluR5. The multiparametric optimization of the initial starting point which ended in the selection of potential clinical candidates combining the best pharmacophoric features is presented. The pharmacological properties are reported and support the interest of these agents for new therapeutic approaches. Furthermore, a summary of the diverse mGluR5 Positron Emission Tomography (PET) radioligands is reported.

High quality gamete production in males and females requires the pituitary gonadotropin follicle stimulating hormone (FSH). In this report a novel chemical class of small molecule inhibitors of FSH receptor (FSHR) is described. ADX61623, a negative allosteric modulator (NAM), increased the affinity of interaction between (125)I-hFSH and human FSHR (hFSHR) five fold. This form of FSHR occupied simultaneously by FSH and ADX61623 was inactive for cAMP and progesterone production in primary cultures of rat granulosa cells. In contrast, ADX61623 did not block estrogen production. This demonstrates for the first time, biased antagonism at the FSHR. To determine if ADX61623 blocked FSH induction of follicle development in vivo, a bioassay to measure follicular development and oocyte production in immature female rats was validated. ADX61623 was not completely effective in blocking FSH induced follicular development in vivo at doses up to 100mg/kg as oocyte production and ovarian weight gain were only moderately reduced. These data illustrate that FSHR couples to multiple signaling pathways in vivo. Suppression of one pool of FSHR uncouples Gαs and cAMP production, and decreases progesterone production. Occupancy of another pool of FSHR sensitizes granulosa cells to FSH induced estradiol production. Therefore, ADX61623 is a useful tool to investigate further the mechanism of the FSHR signaling dichotomy. This may lead to a greater understanding of the signaling infrastructure which enables estrogen biosynthesis and may prove useful in treating estrogen dependent disease.

Compound 1 obtained by random screening and displaying a micromolar activity on the mu opiate receptor was chosen as a starting point for optimization. Two complementary concepts of similarity were used for the design of analogues and compared. These are based, respectively, on a computer-aided comparison of pharmacophoric patterns and on topological similarity. The structure-activity relationships are discussed in light of both similarity concepts. Compound 40, an N-methyl-3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decyl)acetamide derivative, designed by combining the structure-activity relationships enlightened by each method, has a subnanomolar affinity for mu (h) receptor (IC(50) = 0.9 nM). It is a promising lead, allowing the design of a new series of analogues substituted at the N-3 of the spirocycle moiety.

Two compounds, obtained by random screening, and displaying micromolar activities on the mu opiate receptor were used as starting points for optimization. In that work, the traditional concept of the activity of a compound (related to one or a few targets) was extended to the comprehensive pharmacological profile of that compound on more than 70 receptors, transporters, and channels relevant to a CNS-oriented project. Using the two complementary design strategies based on two similarity concepts described in the previous paper, we have obtained analogues with IC(50) values ranging between 0.9 nM and a few micromolar on the mu receptor and displaying qualitatively different profiles. We discuss here, both on a case-by-case basis and from a statistical standpoint, the pharmacological profiles in light of the two similarity concepts.

A series of symmetrically substituted 1,4-bis(3-aminopropyl)piperazines was synthesized and tested towards trypanothione reductase and for its in vitro trypanocidal potency. The most trypanocidal amongst them was found to be totally inactive towards the enzyme and thus constitutes a lead structure for the identification of new potential Trypanosoma cruzi target(s).

Several spermine and spermidine derivatives containing 2-amino diphenylsulfide substituents were prepared and tested for their inhibiting effects on Trypanosoma cruzi trypanothione reductase. IC50 values were assessed between 0.3 and 3 μM. Compound 32 (Ki = 0.4 μM) is the most potent TR inhibitor described so far.

A molecular modeling study meant to detect pharmacophore-like patterns in the active site of trypanothione reductase (TR) offered hints about the opportunity of synthesizing and testing diphenylsulfide derivatives with prolonged or branched polyamino side chains as putative TR inhibitors. The inhibition results within the synthesized series confirmed the main working hypothesis inspired by the molecular modeling study. The different compounds were tested in vitro on the enzyme and on Trypanosoma cruzi and Trypanosoma brucei trypomastigotes as well as in vivo in infected mice.