Merck Sharp + Dohme Corp.

Merck + Co., Inc.

Boyoung Kim

Matthew G Stanton

John S Wai

Rob Burke

Steven L Colletti

Thomas Joseph Tucker

Weimin Wang

Rubina G Parmar

David M Tellers

Thorsten E Fisher

Kathleen B Calati

Linghang Zhuang

Melissa S Egbertson

Mark W Embrey

Terry A Lyle

Donnette D Staas

Catherine M Wiscount

Jeffrey G Aaronson

Joseph P Vacca

John M Sanders

Mark T Bilodeau

John A McCauley

Peter D Williams

Thomas J Greshock

Hemaka Anthony Rajapakse

Lou Anne Neilson

Lekhanh O Tran

Vanessa L Rada

H Marie Langford

Heather E Stevenson

Jonathan T Kern

Kelly L Savage

Jeffery G Aaronson

Disclosed herein is a method for inhibiting expression of a gene of a subject comprising administering (1) a composition comprising R-(L)-(G); wherein R is an oligonucleotide selected from the group consisting of DNA, RNA, siRNA, and microRNA; L is a linker and each occurrence of L is independently selected from Table 3; G is a targeting ligand and each occurrence of G is independently selected from Table 4; each of a and b is independently 0, 1, 2, 3 or 4; and (2) a composition comprising (P)-(L)-(G); wherein P is a peptide and each occurrence of P is independently selected from Table 2; L is a linker and each occurrence of L is independently selected from Table 3; G is a targeting ligand and each occurrence of G is independently selected from Table 4; d is 0, 1, 2, 3, 4, 5 or 6; and each of c and e is independently 1, 2, 3, 4, 5 or 6. Compositions in (1) and (2) can be co-administered or sequentially administered.

Dual molecular delivery of oligonucleotides and peptide containing conjugates

Disclosed herein is a peptide containing conjugate comprising (P)-(L)-(G), wherein P is a peptide and each occurance of P is independently selected from Table 2; L is an optional linker and each occurance of L, if present, is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; d is 0, 1, 2, 3, 4, 5 or 6; and each of c and e is independently 1, 2, 3, 4, 5 or 6. The conjugate can be administered to a subject either alone or in combination with a composition comprising R-(L)-(G), wherein R is an oligonucleotide as defined herein, to inhibit expression of a gene of the subject.

Peptide containing conjugates for dual molecular delivery of oligonucleotides

Disclosed are compounds of Formula (I): and the pharmaceutically acceptable salts thereof, wherein 'A' is S&#x2014;; &#x2014;SO&#x2014;, &#x2014;SO&#x2014;, &#x2014;O&#x2014; or NR&#x2014;, wherein Rac is H, or Calkyl and Rthrough Rare defined herein. Also disclosed are pharmaceutical formulations comprising a compound of Formula I and methods of treating, managing, or ameliorating diseases amenable to treatment, management, or amelioration by inhibition of LRRK2 kinase activity, for example, Parkinson's disease. 

Leucine-rich repeat kinase enzyme activity

Hydroxy-substituted pyrazinopyrrolopyridazine dione compounds are inhibitors of HIV integrase and inhibitors of HIV replication. In one embodiment, the dione compounds are of Formula (I) wherein R, R, R, R, R, Rand Rare defined herein. The compounds are useful in the prevention and treatment of infection by HIV and in the prevention, delay in the onset, and treatment of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. 

HIV integrase inhibitors

8,9-Dihydroxydihydropyridopyrazine-1,6-diones and 8,9-dihydroxypyridopyrazine-1,6-diones are inhibitors of HIV integrase and inhibitors of HIV replication. In one embodiment, the pyridopyrazinediones are of Formula (I): (I), wherein R, R, R, Rand Rare defined herein. The compounds are useful in the prevention and treatment of infection by HIV and in the prevention, delay in the onset, and treatment of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of preventing, treating or delaying the onset of AIDS and methods of preventing or treating infection by HIV are described. 

Dihydroxypyridopyrazine-1,6-dione compounds useful as HIV integrase inhibitors

Hydroxy-substituted pyridopyrrolopyrazine dione compounds are inhibitors of HIV integrase and inhibitors of HIV replication. In one embodiment, the dione compounds are of Formula (I): (I) wherein a, b, A, B, R, R, R, R, R, R, Rand Rare defined herein. The compounds are useful in the prevention and treatment of infection by HIV and in the prevention, delay in the onset, and treatment of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. 

Hydroxy pyridopyrrolopyrazine dione compounds useful as HIV integrase inhibitors

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Lansdale, PA, United States of America

Boyoung Kim