LY2951742 is a high affinity, neutralizing antibody to CGRP. Neutralization of CGRP is efficacious in several OA pain models and works independently of NSAID mechanisms of action. LY2951742 holds promise for the treatment of pain in OA patients.

We identified a large number of differentially expressed genes in the articular cartilage of the MT model. While there was lack of overall identity in cartilage gene expression between the rat models and human OA, several key biological processes were recapitulated in the rat MT OA model.

Intra-articular injection of LPA caused knee joint neuropathy, joint damage and pain. Pharmacological blockade of LPA receptors inhibited joint nerve damage and hindlimb incapacitance. Thus, LPA is a candidate molecule for the development of OA nerve damage and the origin of joint neuropathic pain.

ABSTRACT:In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC 50 of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstrated favorable potency (IC 50 = 2 nM), PK properties, and a robust PK/PD relationship. KEYWORDS: Autotaxin, tool molecule, osteoarthritis, LPA O steoarthritis (OA) is a highly prevalent disease affecting many adults including more than one out of three individuals aged 65 or older in the United States.1 In addition to significant accompanying pain, OA frequently leads to pronounced disability resulting in the loss of work, hospitalization, and joint replacement procedures.2 Current first-line pharmacological treatment options for OA focus on reducing inflammation and the associated pain. Nonsteroidal antiinflammatory drugs (NSAIDS) and selective COX-2 inhibitors are among the most prescribed medications for OA pain but unfortunately are also frequently accompanied by gastrointestinal, renal, and CV side effects, limiting their use. 3 Recently, the role of lyosophosphatidic acid (LPA) in certain inflammatory conditions has been studied. 4 LPA exists as a number of molecular species that have variable saturated and unsaturated fatty acid chains.5 Signaling of LPA through six GPCRs (LPA Receptors 1−6) has been shown to lead to the upregulation of inflammatory cytokines and matrix metalloproteinases, which contribute to the pathogenesis of OA. 6LPA signaling has also been associated with many other pathologies, such as pulmonary fibrosis and cancer. In vivo, the enzyme autotaxin (ATX), with lyosophosopholipase D activity, is the primary source of extracellular LPA, which results from the cleavage of choline from lysophosphatidylcholine (LPC) (Figure 1). LPA is also produced through action of secreted phospholipases A2 (sPLA2) on phosphatidic acid (PA), although this is believed to be a minor route of extracellular LPA production in vivo. 8,9 Autotaxin is an extracellular, 125 kDa protein that was originally characterized in 1993 by Stracke et al. as a motility stimulating protein. 10 In 2002, Umezu-Goto and co-workers demonstrated that ATX was the same protein as a known lysophopholipase D enzyme, which catalyzed the conversion of LPC to LPA.11 Autotaxin is a multidomain protein with two Nterminal somatomedin B-like domains, a centrally located phosphodiesterase domain, and a catalytically inactive nuclease-like domain on the C-terminal region. It is expressed in four main isoforms (ATXα−δ) with largely unknown differential functionality in vivo.7 The catalytic domain of ATX comprises two zinc ions coordinated with histidine and aspartic acid residues with a threonine alcohol serving as the nucleophile. A large hydro...

A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5 are zinc metalloproteases commonly referred to as aggrecanase-1 and aggrecanase-2, respectively. These enzymes are involved in the degradation of aggrecan, a key component of cartilage. Inhibitors of these enzymes could be potential osteoarthritis (OA) therapies. A series of hydantoin inhibitors of ADAMTS-4 and ADAMTS-5 were identified from a screening campaign and optimized through structure-based drug design to give hydantoin 13. Hydantoin 13 had excellent selectivity over other zinc metalloproteases such as TACE, MMP2, MMP3, MMP13, and MMP14. The compound also produced efficacy in both a chemically induced and surgical model of OA in rats.