Sevgi B. Rodan

The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K.

Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclinical species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors.

Involvement of αvβ3 integrins in osteoclast function

Integrins are heterodimeric adhesion receptors that mediate cell–matrix interaction. Osteoclast exhibits high expression of the αvβ3 integrin, which binds to a variety of extracellular matrix proteins including vitronectin, osteopontin, and bone sialoprotein. Arg-Gly-Asp (RGD)-containing peptides, RGD-mimetics, and blocking antibodies to αvβ3 integrin were shown to inhibit bone resorption in vitro and in vivo, suggesting that this integrin may play an important role in regulating osteoclast function. Several lines of evidence have demonstrated that a number of signaling molecules are involved in the αvβ3 integrin-dependent signaling pathway, including c-Src, Pyk2, c-Cbl, and p130Cas. In this article, we review the history of “αvβ3 integrin and osteoclasts” and discuss the involvement of αvβ3 integrins in osteoclast function at tissue, cellular, and molecular levels. A better understanding of the role of αvβ3 integrin in osteoclastic bone resorption would provide opportunities for developing new therapeutics to treat human bone diseases, including rheumatoid arthritis, osteoporosis, and periodontal disease.

Involvement of alpha(v)beta3 integrins in osteoclast function.

Integrins are heterodimeric adhesion receptors that mediate cell–matrix interaction. Osteoclast exhibits high expression of the αvβ3 integrin, which binds to a variety of extracellular matrix proteins including vitronectin, osteopontin, and bone sialoprotein. Arg-Gly-Asp (RGD)-containing peptides, RGD-mimetics, and blocking antibodies to αvβ3 integrin were shown to inhibit bone resorption in vitro and in vivo, suggesting that this integrin may play an important role in regulating osteoclast function. Several lines of evidence have demonstrated that a number of signaling molecules are involved in the αvβ3 integrin-dependent signaling pathway, including c-Src, Pyk2, c-Cbl, and p130Cas. In this article, we review the history of “αvβ3 integrin and osteoclasts” and discuss the involvement of αvβ3 integrins in osteoclast function at tissue, cellular, and molecular levels. A better understanding of the role of αvβ3 integrin in osteoclastic bone resorption would provide opportunities for developing new therapeutics to treat human bone diseases, including rheumatoid arthritis, osteoporosis, and periodontal disease.

Nonpeptide αvβ3 antagonists. Part 2: constrained glycyl amides derived from the RGD tripeptide

Abstract Mimetics of the RGD tripeptide are described that are potent, selective antagonists of the integrin receptor, αvβ3. The use of the 5,6,7,8-tetrahydro[1,8]naphthyridine group as a potency-enhancing N-terminus is demonstrated. Two 3-substituted-3-amino-propionic acids previously contained in αIIbβ3 antagonists were utilized to enhance binding affinity and functional activity for the targeted receptor. Further affinity increases were then achieved through the use of cyclic glycyl amide bond constraints.

Non-Peptide αvβ3 Antagonists. Part 4: Potent and Orally Bioavailable Chain-Shortened RGD Mimetics

Abstract Potent non-peptidic α v β 3 antagonists have been prepared where deletion of an amide bond from an earlier series of linear RGD-mimetics provides a novel series of chain-shortened α v β 3 antagonists with significantly improved oral pharmacokinetics. These chain-shortened α v β 3 antagonists represent structurally novel integrin inhibitors.

The Role of Prostaglandins in Bone Formation

Prostaglandins of the E series have been shown to be effective inducers of bone formation in vivo. In this study, the effects of PGE2 were evaluated in vivo using subcutaneous administration (3 mg/kg/d for 25 days) to ovariectomized rats or local application in the marrow cavity of tibiae of rats using biodegradable implants (0.13, 1.4 and 32 microg released over 8 days). Systemic treatment of rats with PGE2 stimulated cancellous bone formation in the metaphysis of the proximal tibiae as well as endocortical bone formation and de novo trabecular bone formation in the marrow cavity. Local delivery of PGE2 increased cancellous bone volume in the secondary spongiosa and cortical thickness (at 32 microg). Comparisons of prostanoid effects in vitro, in a bone-derived cell line, showed that PGF2alpha was a better stimulator of DNA synthesis than PGE2. PGF2alpha increased the steady state levels of IGF-I receptor mRNA while PGE2 increased IGF-I expression. Although the mechanism of bone formation by PGE2 is not known at this time, it is clear that PGE2 has powerful local anabolic effects on bone formation in vivo possibly by mediating responses to signals such as changes in mechanical force.

The discovery of MK-0674, an orally bioavailable cathepsin K inhibitor

MK-0674 is a potent and selective cathepsin K inhibitor from the same structural class as odanacatib with a comparable inhibitory potency profile against Cat K. It is orally bioavailable and exhibits long half-life in pre-clinical species. In vivo studies using deuterated MK-0674 show stereoselective epimerization of the alcohol stereocenter via an oxidation/reduction cycle. From in vitro incubations, two metabolites could be identified: the hydroxyleucine and the glucuronide conjugate which were confirmed using authentic synthetic standards.

Peptidic 1-cyanopyrrolidines: Synthesis and SAR of a series of potent, selective cathepsin inhibitors

1-Cyanopyrrolidines have previously been reported to inhibit cysteinyl cathepsins (Falgueyret, J.-P. et al., J. Med. Chem. 2001, 44, 94). In order to optimize binding interactions for a given cathepsin and simultaneously reduce interactions with the other closely related enzymes, small peptidic substituents were introduced to the 1-cyanopyrrolidine scaffold, either at the 2-position starting with proline or at the 3-position of aminopyrrolidines. The resulting novel compounds proved to be micromolar inhibitors of cathepsin B (Cat B) but nanomolar to picomolar inhibitors of cathepsins K, L, and S (Cat K, Cat L, Cat S). Several of the compounds were >20-fold selective versus the other three cathepsins. SAR trends were observed, most notably the remarkable potency of Cat L inhibitors based on the 1-cyano-D-proline scaffold. The selectivity of one such compound, the 94 picomolar Cat L inhibitor 12, was demonstrated at higher concentrations in DLD-1 cells. Although none of the compounds in the proline series that was tested proved to be submicromolar in the in vitro bone resorption assay, two Cat K inhibitors in the 3-substituted pyrrolidine series, 24 and 25 were relatively potent in that assay.

Non-Peptide αvβ3 antagonists. Part 6: Design and synthesis of αvβ3 antagonists containing a pyridone or pyrazinone central scaffold

Abstract Two novel series of small-molecule RGD mimetics containing either a substituted pyridone or pyrazinone central constraint were prepared. Modification of the β-alanine 3-substituent produced compounds that are potent and selective α v β 3 antagonists and exhibit a range of physicochemical properties.

Disposition of a novel and potent αvβ3 antagonist in animals, and extrapolation to man

1.u2002The disposition of 3-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) propyl]-imidazolidin-1-yl}-3(S)-(6-methoxy-pyridin-3-yl)propionic acid (compound A), a potent and selective αvβ3 antagonist, was characterized in several animal species in support of its selection for preclinical safety studies and potential clinical development. 2.u2002Compound A exhibited marked species differences in pharmacokinetics; the plasma clearances and bioavailabilities ranged from 33–47u2009mlu2009min−1u2009kg−1 in rats and mice to 4–9u2009mlu2009min−1u2009kg−1 in dogs and monkeys, and about 20% in rats to 70–80% in dogs and monkeys, respectively. Both the intravenous (i.v.) and oral kinetics of compound A were linear over the dose range studied in dogs (0.1–5u2009mgu2009kg−1 i.v. and 0.25–20u2009mgu2009kg−1 orally [p.o.]) and rats (1–30u2009mgu2009kg−1 i.v. and 4–160u2009mgu2009kg−1 p.o.). 3.u2002Compound A was eliminated substantially by urinary excretion; the urinary recovery of the unchanged drug was 67% in rhesus, 48% in dogs and about 30% in rats. In these animal species, biotransformation was modest. 4.u2002Following i.v. administration of [14C]-compound A to rats, the radioactivity rapidly distributed to all tissues investigated, with high levels of the radioactivity detected in liver, kidney and intestine soon after the drug administration. The radioactivity declined rapidly, with less than 1% of the i.v. dose remaining at 30-h post-dose. 5.u2002Compound A was moderately bound to plasma proteins, with unbound fractions of 26, 20, 14 and 5% for rats, dogs, monkeys and humans, respectively. It was bound primarily to human α1-acid glycoprotein (about 85% binding at 0.1% concentration), as compared with human albumin (<u200950% binding at 4% concentration). 6.u2002Using simple allometry, compound A was predicted to exhibit relatively low clearance (1–3u2009mlu2009min−1u2009kg−1) and low volume of distribution (0.1–0.3 lu2009kg−1) in humans. Based on the predicted values, compound A was projected to exhibit a favourable oral pharmacokinetic profile in humans, with good bioavailability (50–80%). These predicted values provided a basis for compound selection for further development.