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The Th17 pathway has been implicated in autoimmune diseases. The retinoic acid receptor-related orphan receptor C2 (RORγt) is a master regulator of Th17 cells and controls the expression of IL-17A. RORγt is expressed primarily in IL-17A-producing lymphoid cells. Here we describe a virtual screen of the ligand-binding pocket and subsequent screen in a binding assay that identified the 1-benzyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3- c ]pyran]-2'-carboxamide scaffold as a starting point for optimization of binding affinity and functional activity guided by structure-based design. Compound 12 demonstrated activity in a mouse PK/PD model and efficacy in an inflammatory arthritis mouse model that were used to define the level and duration of target engagement required for efficacy in vivo . Further optimization to improve ADME and physicochemical properties with guidance from simulations and modeling provided compound 22 , which is projected to achieve the level and duration of target engagement required for efficacy in the clinic.

Rho kinase is an important target implicated in a variety of cardiovascular diseases. Herein, we report the optimisation of the fragment derived ATP-competitive ROCK inhibitors 1 and 2 into lead compound 14A. The initial goal of improving ROCK-I potency relative to 1, whilst maintaining a good PK profile, was achieved through removal of the aminoisoquinoline basic centre. Lead 14A was equipotent against both ROCK-I and ROCK-II, showed good in vivo efficacy in the spontaneous hypertensive rat model, and was further optimised to demonstrate the scope for improving selectivity over PKA versus hydroxy Fasudil 3., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Fragment-based NMR screening of a small literature focused library led to identification of a historical thrombin/FactorXa building block, 17A, that was found to be a ROCK-I inhibitor. In the absence of an X-ray structure, fragment growth afforded 6-substituted isoquinolin-1-amine derivatives which were profiled in the primary ROCK-I IMAP assay. Compounds 23A and 23E were selected as fragment optimized hits for further profiling. Compound 23A has similar ROCK-1 affinity, potency and cell based efficacy to the first generation ROCK inhibitors, however, it has a superior PK profile in C57 mouse. Compound 23E demonstrates the feasibility of improving ROCK-1 affinity, potency and cell based efficacy for the series, however, it has a poor PK profile relative to 23A., (Copyright © 2010. Published by Elsevier Ltd.)

Hit compound 1, a selective noradrenaline re-uptake transporter (NET) inhibitor was optimised to build in potency at the serotonin re-uptake transporter (SERT) whilst maintaining selectivity against the dopamine re-uptake transporter (DAT). During the optimisation of 1 it became clear that selectivity against the Kv11.1 potassium ion channel (hERG) was also a parameter for optimisation within the series. Discrete structural changes to the molecule as well as a lowering of global cLogP successfully increased the hERG selectivity to afford compound 11 m, which was efficacious in a mouse model of inflammatory pain, complete Freund's adjuvant (CFA) induced thermal hyperalgesia and a rat model of neuropathic pain, spinal nerve ligation (SNL) induced mechanical allodynia., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Bicyclic piperazine derivatives were synthesized as conformationally constrained analogs of N-alkyl piperazines and were found to be potent CB1 receptor agonists. The CB1 receptor agonist activity was dependent upon the absolute configuration of the chiral center of the bicyclic ring system. Although the conformational constraint did not protect the compounds from metabolism by N-dealkylation, several bicyclic analogs were found to be more potent than the unconstrained lead compound. Compound 8b demonstrated potent antinociceptive activity in vivo., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

It has been widely recognised over the recent years that parallel modulation of multiple biological targets can be beneficial for treatment of diseases with complex etiologies such as cancer asthma, and psychiatric disease. In this article, current strategies for the generation of ligands with a specific multi-target profile (designed multiple ligands or DMLs) are described and a number of illustrative example are given. Designing multiple ligands is frequently a challenging endeavour for medicinal chemists, with the need to appropriately balance affinity for 2 or more targets whilst obtaining physicochemical and pharmacokinetic properties that are consistent with the administration of an oral drug. Given that the properties of DMLs are influenced to a large extent by the proteomic superfamily to which the targets belong and the lead generation strategy that is pursued, an early assessment of the feasibility of any given DML project is essential.

Modulating multiple protein targets simultaneously can be beneficial for treating complex diseases. The redundancy that exists within biological networks means that modulating single proteins might not be sufficient to produce the desired efficacy while, at the same time, minimizing adverse effects. Designing multi-target drugs can be challenging for medicinal chemists, with current lead-discovery strategies often producing large, complex molecules with low ligand efficiency and poor oral bioavailability. Paradoxically, analyses of the relationship between the selectivity of biologically active compounds and their molecular size suggest that promiscuous compounds should typically be smaller than target-selective compounds. A fragment-based approach to multi-target drug discovery could lead to a new generation of compounds with improved physicochemical and pharmacokinetic properties.

Compounds designed to bind more than one target can provide a therapeutic benefit relative to highly target-selective ligands. The physicochemical properties of designed multiple ligands were found to be less druglike than those for preclinical compounds in general. These properties are controlled by the superfamily to which the targets belong and the lead discovery strategy that was followed. The properties for peptide G-protein-coupled receptor (GPCR) ligands were the least favorable for oral delivery, whereas transporter, monoamine GPCR, and oxidase ligands were the most druglike. The lead discovery strategy, framework combination or screening, exerts a profound influence on the property values. Combining the frameworks from two selective ligands often results in large, complex dual ligands, but druglike ligands can be achieved if the degree of framework overlap is maximized and the size of the selective ligands minimized. For some target combinations, a screening approach may provide a route to smaller, less complex leads.

The target families of greatest interest in drug discovery can be differentiated on the basis of the physicochemical properties of their pre-clinical ligands. The ligands for peptidergic targets, such as peptide GPCRs and integrin receptors, possess significantly higher median property values than those for aminergic targets, such as monoamine transporters and GPCRs. The ligands for peptide GPCRs were found to be less efficient, in terms of their binding energy per unit of molecular weight or lipophilicity, than ligands for monoamine GPCRs. The changes in the property values during the optimization process were found to vary only slightly across the target families, with the main determinant of the drug-likeness of the optimized compounds being the profile of the starting compounds. Agonists for monoamine GPCRs, opioid receptors and ion channels were typically smaller and less lipophilic than the antagonists, but there was no difference between the agonists and the antagonists for peptide GPCRs and nuclear receptors.

Increasingly, it is being recognised that a balanced modulation of several targets can provide a superior therapeutic effect and side effect profile compared to the action of a selective ligand. Rational approaches in which structural features from selective ligands are combined have produced designed multiple ligands that span a wide variety of targets and target classes. A key challenge in the design of multiple ligands is attaining a balanced activity at each target of interest while simultaneously achieving a wider selectivity and a suitable pharmacokinetic profile. An analysis of literature examples reveals trends and insights that might help medicinal chemists discover the next generation of these types of compounds.

In this study, we describe the activity of CT1746, an orally-active synthetic MMP inhibitor that has a greater specificity for gelatinase A, gelatinase B and stromelysin than for interstitial collagenase and matrilysin, in a nude mouse model that better mimics the clinical development of human colon cancer. The model is constructed by surgical orthotopic implantation (SOI) of histologically-intact tissue of the metastatic human colon tumor cell line Co-3. Animals were gavaged with CT1746 twice a day at 100 mg/kg for 5 days after the SOI of Co-3 for 43 days. In this model CT1746 significantly prolonged the median survival time of the tumor-bearing animals from 51 to 78 days. Significant efficacy of CT1746 was observed on primary tumor growth (32% reduction in mean tumor area at day 36), total spread and metastasis (6/20 treated animals had no detectable spread and metastasis at autopsy compared to 100% incidence of secondaries in control groups). Efficacy of CT1746 could also be seen on reducing tumor spread and metastasis to individual organ sites such as the abdominal wall, cecum and lymph nodes compared to vehicle and untreated controls. We conclude that chronic administration of a peptidomimetic MMP inhibitor via the oral route is feasible and results in inhibition of solid tumor growth, spread and metastasis with increase in survival in this model of human cancer, thus converting aggressive cancer to a more controlled indolent disease.