James J. Perkins

Synthesis of 2-(alkylamino)benzimidazoles

Abstract A general and highly convenient procedure for the synthesis of 2-(alkylamino)benzimidazoles has been developed and a variety of analogs have been efficiently prepared. Included is a dipeptide mimetic in which the guanidine group of an arginine residue has been replaced with a 2-aminobenzimidazole.

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.

Discovery of the Selective Androgen Receptor Modulator MK-0773 Using a Rational Development Strategy Based on Differential Transcriptional Requirements for Androgenic Anabolism Versus Reproductive Physiology

Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize the AR, but how these complex activities translate into tissue selectivity is not known. Here, we probed receptor function using >1000 synthetic AR ligands. These compounds produced a spectrum of activities in each assay ranging from 0 to 100% of maximal response. By testing different classes of compounds in ovariectomized rats, we established that ligands that transactivated a model promoter 40–80% of an agonist, recruited the coactivator GRIP-1 <15%, and stabilized the N-/C-terminal interdomain interaction <7% induced bone formation with reduced effects in the uterus and in sebaceous glands. Using these criteria, multiple SARMs were synthesized including MK-0773, a 4-aza-steroid that exhibited tissue selectivity in humans. Thus, AR activated to moderate levels due to reduced cofactor recruitment, and N-/C-terminal interactions produce a fully anabolic response, whereas more complete receptor activation is required for reproductive effects. This bimodal activation provides a molecular basis for the development of SARMs.

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.

Discovery of selective glucocorticoid receptor modulator MK-5932.

A series of partial agonists of the Glucocorticoid Receptor were prepared targeting reduced transactivation activity, while maintaining significant transrepression activity. Incorporation of an ortho-aryl amide produced compounds with the desired in vitro profile. Bioreactors consisting of Suspension cultures of Sf21 cells co expressing a CYP3A4 and NADPH-cytochrome P450 oxireductase were used to prepare the major metabolites of these compounds and revealed that oxidative N-dealkylation provided a pathway for formation of metabolites that were more agonistic than the parent partial agonists. Oxidative N-dealkylation was blocked in a new series of compounds, however oxidation alone was capable of producing full agonist metabolites. Incorporation of an ortho-primary amide and utilization of fluorine to modulate agonism afforded partial agonist MK-5932. Synthesis of the major metabolites of MK-5932 using bioreactor technology revealed that no significant GR-active metabolites were formed. Orally administered MK-5932 displayed anti-inflammatory efficacy in a Rat Oxazolone-induced chronic dermatitis model, while sparing plasma insulin.

Identification of an anabolic selective androgen receptor modulator that actively induces death of androgen-independent prostate cancer cells.

Prostate cancer (PCa) initially responds to inhibition of androgen receptor (AR) signaling, but inevitably progresses to hormone ablation-resistant disease. Much effort is focused on optimizing this androgen deprivation strategy by improving hormone depletion and AR antagonism. However we found that bicalutamide, a clinically used antiandrogen, actually resembles a selective AR modulator (SARM), as it partially regulates 24% of endogenously 5α-dihydrotestosterone (DHT)-responsive genes in AR(+) MDA-MB-453 breast cancer cells. These data suggested that passive blocking of all AR functions is not required for PCa therapy. Hence, we adopted an active strategy that calls for the development of novel SARMs, which induce a unique gene expression profile that is intolerable to PCa cells. Therefore, we screened 3000 SARMs for the ability to arrest the androgen-independent growth of AR(+) 22Rv1 and LNCaP PCa cells but not AR(-) PC3 or DU145 cells. We identified only one such compound; the 4-aza-steroid, MK-4541, a potent and selective SARM. MK-4541 induces caspase-3 activity and cell death in both androgen-independent, AR(+) PCa cell lines but spares AR(-) cells or AR(+) non-PCa cells. This activity correlates with its promoter context- and cell-type dependent transcriptional effects. In rats, MK-4541 inhibits the trophic effects of DHT on the prostate, but not the levator ani muscle, and triggers an anabolic response in the periosteal compartment of bone. Therefore, MK-4541 has the potential to effectively manage prostatic hypertrophic diseases owing to its antitumor SARM-like mechanism, while simultaneously maintaining the anabolic benefits of natural androgens.

Nonpeptide glycoprotein IIB/IIIA inhibitors. 19. A new design paradigm employing linearly minimized, centrally constrained, exosite inhibitors.

A new series of potent, linearly-minimized, orally active, selective GPIIb/IIIa inhibitors is identified. Thus 15 (L-750,034) achieves interaction via a constrained, non-turned conformation that maintains the proper distance between its charged termini and full sulfonamide exosite interaction. The diminutive stature and the proposed linear conformation of L-750,034 define a new paradigm for the conceptualization of RGD mimics.

The synthesis of [3H]L‐734,217, an orally active fibrinogen receptor antagonist

The synthesis of [ 3 H]L-734,217, 1b, an orally active fibrinogen receptor antagonist, is described. The conversion of 3-amino crotonate 6 to [ 3 H]L-734,217 was carried out via a two step sequence of catalytic tritiation followed by basic hydrolysis. Deuterium model reactions showed that the reduction of 6 with PtO2 occurred via hydrogen transfer from the solvent (ethanol or acetic acid) leading to poor isotope incorporation. When this reduction was conducted in methanol with 10% Pd/C, good isotope incorporation resulted. Ultimately, [ 3 H]L-734,217 was formed with a specific activity of 42 Ci/mmol.